CN102417508A - Fused-aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto - Google Patents
Fused-aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto Download PDFInfo
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- CN102417508A CN102417508A CN2011103168320A CN201110316832A CN102417508A CN 102417508 A CN102417508 A CN 102417508A CN 2011103168320 A CN2011103168320 A CN 2011103168320A CN 201110316832 A CN201110316832 A CN 201110316832A CN 102417508 A CN102417508 A CN 102417508A
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- 0 CC(C1)C1S1/C(/C(C)CC(C2C3CCCCC2)C3C2**N3*CCCC(*)CC3)=C/CC2C2(C)*(C3)=*C1=C3CCC2 Chemical compound CC(C1)C1S1/C(/C(C)CC(C2C3CCCCC2)C3C2**N3*CCCC(*)CC3)=C/CC2C2(C)*(C3)=*C1=C3CCC2 0.000 description 6
- NFJPEKRRHIYYES-UHFFFAOYSA-N C=C1CCCC1 Chemical compound C=C1CCCC1 NFJPEKRRHIYYES-UHFFFAOYSA-N 0.000 description 1
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
- A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
Abstract
The present invention relates to certain fused aryl and heteroaryl derivatives of Formula (I) that are modulators of metabolism. Accordingly, compounds of the present invention are useful in the prophylaxis or treatment of metabolic disorders and complications thereof, such as, diabetes and obesity.
Description
The present invention is to be that July 13, application number in 2004 are that 200480020172 X, denomination of invention are as the fused-aryl of modulators of metabolism and dividing an application of heteroaryl derivative and prevention and the relative illness patent of treatment the applying date.
Technical field
The present invention is specific fused-aryl and heteroaryl derivative about the glucose metabolism regulator.Therefore, compound of the present invention is used for prevention or treatment metabolism disorder and its complication, for example mellitus and obesity.
Background technology
Mellitus are a kind of serious diseases that surpass 100,000,000 populations in the world wide that torment.In the U.S., 12,000,000 diabetic subject of surpassing is arranged, and 600,000 new diagnosed SARS cases are arranged every year.
Mellitus are the diagnosis terms that are characterized as one type of illness of the glucose homoeostasis unusual (abnormal glucose homeostasis) that causes hyperglycemia.Mellitus have many types, but modal two kinds is type i diabetes (being also referred to as insulin-dependent diabetes mellitus or IDDM) and type ii diabetes (being also referred to as non insulin dependent diabetes or NIDDM).
The cause of disease of dissimilar mellitus is also different; Yet each diabetic subject has different symptom identical: liver glucose production surplus and less ability or do not have ability with during glucose is from the blood transfer to the cell, glucose becomes the primary fuel of health in cell.
The people who does not suffer from mellitus relies on Regular Insulin, and the hormone that promptly a kind of pancreas produces is with during glucose is from the blood transfer to the soma.Yet the Regular Insulin that the diabetic subject does not produce Regular Insulin or can not effectively use them to produce; Therefore they can not move into glucose in its cell.Glucose accumulates in and causes the symptom that is called hyperglycemia in the blood, and passing in time can cause the serious health problem.
Mellitus are a kind of have dependency metabolism, vascular and neuropathy pathology ramose syndromess.Said metabolic syndrome general feature is a hyperglycemia, comprises by the insulin secretion and/or the caused glucide of invalid insulin action, fat and the protein metabolization that do not have or significantly reduce.Said vascular syndromes is cardiovascular by causing, the aberrant angiogenesis of retina and renal complication is formed.Periphery and autonomic nervous system also are the part of diabetic syndrome unusually.
Accounting for about 5% to 10% the IDDM patient of mellitus number of patients does not produce Regular Insulin and therefore must keep its glucose level normal by insulin injection.IDDM be characterized as the pancreatic beta cell that produces Regular Insulin be damaged caused endogenous insulin generate content low or detect less than, said characteristic makes a distinction IDDM and NIDDM the most easily.Once the IDDM that was called juvenile onset diabetes attacks youth and old man equally.
About 90% to 95% diabetic subject suffers from type ii diabetes (or NIDDM).NIDDM patient produces Regular Insulin, but its intravital cell has the inappropriate response hormone of the said cell of insulin resistance, so glucose accumulates in its blood.NIDDM is characterized as between endogenous insulin generation and the insulin requirements unbalanced relatively, causes higher glucose level.Opposite with IDDM, NIDDM always exists some endogenous insulins to produce; Many NIDDM patients have normal or even higher blood insulin level and insufficient insulin (Rotwein, people N Engl J Med308 such as R, 65-71 (1983)) that other NIDDM patient produces.Most people that suffered from NIDDM by diagnosis were at 30 years old or older, and the half new case was at 55 years old and older.Compare with the Aisa people with white man, NIDDM is more general at U.S. aboriginal, Black American, Latin Americans and Hispanic philtrum.In addition, the morbidity can be insidiousness or or even unconspicuous clinically, thereby make diagnosis very the difficulty.
The initial insulin resistance that the initial not bright yet many people of focus of causing a disease of NIDDM propose peripheral tissues is a primary event.This viewpoint is supported in the research of heredity epidemiology.Equally, having the opinion insulopathic is the initial defective of NIDDM.Might two kinds of important component parts (Rimoin, people Emery and Rimoin ' s Principles and Practice of Medical the 3rd edition 1 1401-1402 of Genetics (1996) such as D L) that phenomenon all is said lysis.
Many NIDDM patients have sedentary lifestyle and stature fat, and the weight that their weight ratio is recommended to its height and physique has more about 20%.In addition, the characteristic of obesity is hyperinsulinemia and insulin resistance (characteristic that NIDDM also has), hypertension and atherosclerosis.
Obesity and mellitus are modal human health problems in the industrialization society.1/3rd population overweight at least 20% in the industrialized country.In the U.S., the per-cent of population of being obese rises to 33% of the early 1990s from 25% of late nineteen seventies.Obesity is one of most important risk factors of NIDDM.The definition of obesity is different, but generally speaking body weight surpasses the weight at least 20% of recommending to his height and physique and just thinks that this patient is fat.Overweight 30% patient suffers from the risk triplication of NIDDM, and 3/4ths NIDDM patient is overweight.
In the laboratory animal and the mankind, obesity is as result unbalance between calorie intake and energy expenditure and insulin resistance and mellitus height correlation.Yet the related molecular mechanism of obesity-diabetic syndrome is still unclear.In the obesity early-stage development process, but increase insulin secretion balance insulin resistance and protect the patient to avoid hyperglycemia (le Stunff waits people Diabetes43,696-702 (1989)).Yet after decades; The β cell function is degenerated and about 20% obese people can be suffered from non insulin dependent diabetes (Pederson, P Diab Metab Rev 5,505-509 (1989)) and (Brancati; People Arch Intern Med 159 such as F L, 957-963 (1999)).In view of obesity is popular in contemporary society, therefore it become the primary risk factors (Hill, people Science 280 such as J O, 1371-1374 (1998)) of NIDDM.Yet, make a part of patient be easy to fat accumulation is reacted and the factor that changes insulin secretion still cannot not be known.
The someone is categorized as overweight still obesity can judges that generally said weight index is by square (m of body weight (kg) divided by height according to its weight index (BMI)
2) calculate.Therefore BMI unit is kg/m
2And might calculate the BMI scope relevant with the each age group minimum mortality.The overweight BMI that is defined as is at 25-30kg/m
2Scope in, and obesity is defined as BMI greater than 30kg/m
2(referring to following table).The problem that this definition exists is that it does not have the body weight ratio of muscle (fatty tissue) that will be relevant with fat to take into account.For this problem is described, also can obesity be defined as according to body fat content, masculinity and femininity is respectively greater than 25% and 30%.
Press weight index (BMI) with weight classification
| BMI | Classification |
| ＜18?5 | Kick the beam |
| 18?5-24?9 | Normally |
| 25?0-29?9 | Overweight |
| 30?0-34?9 | Fat (I class) |
| 35?0-39?9 | Fat (II class) |
| ＞40 | Extreme fat (III class) |
Along with BMI increases, can cause mortality risk to rise with the irrelevant multiple reason of other risk factors.About the modal disease of obesity is cardiovascular diseases (especially being hypertension), mellitus (obesity increases the weight of the development of mellitus), gallbladder disease (especially being cancer) and reproductive disease.Research shows even the moderate reduction body weight just can be corresponding to significantly reducing the risk of suffering from coronary heart disease.
Comprise orlistat (Orlistat) (XENICAL as the commercially available compound of antiobesity agent
TM) and sibutramine (Sibutramine).Orlistat (lipase inhibitor) directly suppresses fat absorbing and is easy to produce the high incidence of bad (though harmless relatively) spinoff (for example diarrhoea).Some patients' of sibutramine (blended 5-HT/ NRI) meeting rising blood pressure and heart rate.Reported thrombotonin releasing agent/reuptake inhibitor fenfluramine (fenfluramine) (Pondimm
TM) and dextrorotation fenfluramine (dexfenfluramine) (Redux
TM) can reduce ingestion of food and body weight through an extended period (greater than 6 months).Yet two kinds of products are all cancelled after the unusual relevant Prima Facie Evidence of application and heart valve of two kinds of products of report.Therefore, need the safer antiobesity agent of exploitation.
Obesity has also significantly increased suffers from cardiovascular disease risk.Coronary insufficiency, atheromatous disease and cardiac insufficiency are positioned at the cardiovascular complication prostatitis of being caused by obesity.If all have ideal body weight per capita according to estimates, so the risk of coronary insufficiency will reduce by 25% and the risk of cardiac insufficiency and apoplexy (cerebral vascular) will reduce by 35%.Overweight 30% less than 50 years old patient in Incidence of CHD double.The diabetic subject faces life-span minimizing 30%.After 45 years old, the diabetic subject has remarkable cardiopathic possibility high about three times and the possibility that suffers stroke up to five times than the people who does not suffer from mellitus.Mutual relationship between NIDDM and coronary heart disease risk factor and the potential value (Perry, people BMJ 310 such as I J, 560-564 (1995)) of preventing the integrated approach of these illnesss based on prevention of obesity are stressed in these discoveries.
Mellitus same with suffer from ephrosis, illness in eye and neural system problem and be implicative of each other.When ephrosis (kidney disease or nephropathy) betides in the impaired and excessive urine that bleeds of protein of " strobe utility " of kidney and final kidney fail.Mellitus also are the first causes of eyes posterior retina damage and increase cataract and glaucomatous risk.Finally, mellitus are relevant with the nerve injury of especially shank and foot, and it can disturb the ability of feels pain and facilitate severe infections.In a word, diabetic complication is a domestic first extremely therefore.
Summary of the invention
The present invention describes and to combine with GPCR (this paper is called RUP3) and regulate the active compound of GPCR and its purposes.Term RUP3 used herein comprises that gene pool (GeneBank) goes into to hide the lineal homologue of the allele variant of the human sequence who finds among registration number XM_066873 and the AY288416, natural generation, Mammals and its recombinant mutant.The preferred human RUP3 that is used for screening and test The compounds of this invention is provided in Seq IDNo 1 nucleotide sequence and the corresponding nucleotide sequence of Seq IDNo2.
One aspect of the present invention contains specific fused-aryl and heteroaryl derivative shown in the formula (I):
Or its pharmaceutically acceptable salt, hydrate or solvolyte;
Wherein
A and B are separately independently for being selected from by C by 1 to 4 according to circumstances
1-3Alkyl, C
1-4Alkoxyl group, carboxyl, cyanic acid, C
1-3The substituted C of the substituting group of the group that alkylhalide group and halogen are formed
1-3Alkylidene group;
D is O, S, S (O), S (O)
2, CR
1R
2Or N-R
2, R wherein
1Be selected from by H, C
1-8Alkyl, C
1-4The group that alkoxyl group, halogen and hydroxyl are formed;
E is N, C or CR
3, R wherein
3Be H or C
1-8Alkyl;
When E is N or CR
3The time
Be singly-bound, or when E is C
Be two keys;
K is C
3-6Cycloalkylidene or C
1-3Alkylidene group, it independently is selected from by C by 1 to 4 separately according to circumstances
1-3Alkyl, C
1-4Alkoxyl group, carboxyl, cyanic acid, C
1-3The substituting group of the group that alkylhalide group and halogen are formed replaces, or K is a key;
Q is NR
4, O, S, S (O) or S (O)
2, R wherein
4Be H or C
1-8Alkyl and C
1-8Alkyl is according to circumstances by C
2-8Dialkylamine replaces;
T is N or CR
5
M is N or CR
6
J is N or CR
7,
U is C or N;
V is N, CR
8Or V is a key;
W is N or C;
X is O, S, N, CR
9Or NR
11
Y is O, S, N, CR
10Or NR
12
Z is C or N,
R
5, R
6, R
7, R
8, R
9And R
10Independently be selected from the .H of group, the C that form by following group separately
1-5Acyloxy, C
2-6Thiazolinyl, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkyl carboxamide groups, C
2-6Alkynyl, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, C
1-4Alkyl urea groups, amino, C
1-4Alkylamino, C
2-8Dialkyl amido, carboxamide groups, cyanic acid, C
3-6Naphthenic base, C
2-6Dialkyl group carboxamide groups, C
2-6Dialkyl group sulfoamido, halogen, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, C
1-4Alkylhalide group sulfinyl, C
1-4Alkylhalide group alkylsulfonyl, C
1-4Alkyl halide sulfenyl, hydroxyl, hydroxyl amino and nitro, wherein said C
2-6Thiazolinyl, C
1-8Alkyl, C
2-6Alkynyl and C
3-6Naphthenic base is replaced by 1,2,3 or 4 substituting group that is selected from the group that is made up of following group according to circumstances: C
1-5Acyl group, C
1-5Acyloxy, C
1-4Alkoxyl group, C
1-4Alkylamino, C
1-4Alkyl carboxamide groups, C
1-4Alkylthio carboxamide groups, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, C
1-4Alkylthio urea groups, C
1-4Alkyl urea groups, amino, carbonyl-C
1-6-alkoxyl group, carboxamide groups, carboxyl, cyanic acid, C
2-8Dialkyl amido, C
2-6Dialkyl group carboxamide groups, C
1-4Two alkylthio carboxamide groups, C
2-6Dialkyl group sulfoamido, C
1-4Alkylthio urea groups, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, C
1-4Alkylhalide group sulfinyl, C
1-4Alkylhalide group alkylsulfonyl, C
1-4Alkylhalide group, C
1-4Alkyl halide sulfenyl, halogen, hydroxyl, hydroxyl amino and nitro;
R
11And R
12Independently be selected from separately according to circumstances by 1,2,3 or 4 substituted C of substituting group that is selected from the group that forms by following group
2-6Thiazolinyl, C
1-8Alkyl, C
2-6Alkynyl or C
3-6Naphthenic base C
1-5Acyl group, C
1-5Acyloxy, C
1-4Alkoxyl group, C
1-4Alkylamino, C
1-4Alkyl carboxamide groups, C
1-4Alkylthio carboxamide groups, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, C
1-4Alkylthio urea groups, C
1-4Alkyl urea groups, amino, carbonyl-C
1-6-alkoxyl group, carboxamide groups, carboxyl, cyanic acid, C
2-8Dialkyl amido, C
2-6Dialkyl group carboxamide groups, C
1-4Two alkylthio carboxamide groups, C
2-6Dialkyl group sulfoamido, C
1-4Alkylthio urea groups, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, C
1-4Alkylhalide group sulfinyl, C
1-4Alkylhalide group alkylsulfonyl, C
1-4Alkylhalide group, C
1-4Alkyl halide sulfenyl, halogen, hydroxyl, hydroxyl amino and nitro;
Ar
1For separately according to circumstances by R
13, R
14, R
15, R
16And R
17Substituted aryl or heteroaryl: R wherein
13Be selected from the group that forms by following group: C
1-5Acyl group, C
1-6Acyl group sulfoamido, C
1-5Acyloxy, C
2-6Thiazolinyl, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkylamino, C
1-6Alkyl carboxamide groups, C
1-4Alkylthio carboxamide groups, C
2-6Alkynyl, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, C
1-4Alkylthio urea groups, C
1-4Alkyl urea groups, amino, aryl sulfonyl, carbamyl imino-, carbonyl-C
1-6-alkoxyl group, carboxamide groups, carboxyl, cyanic acid, C
3-7Naphthenic base, C
3-7Cycloalkyloxy, C
2-6Dialkyl amido, C
2-6Dialkyl group carboxamide groups, C
2-6Two alkylthio carboxamide groups, guanidine radicals, halogen, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, C
1-4Alkylhalide group sulfinyl, C
1-4Alkylhalide group alkylsulfonyl, C
1-4Alkyl halide sulfenyl, heterocyclic radical, heterocyclic radical-oxygen base, heterocyclic radical alkylsulfonyl, heterocyclic radical-carbonyl, heteroaryl, heteroaryl carbonyl, hydroxyl, nitro, C
4-7Ketone group-naphthenic base, phenoxy, phenyl, sulfoamido, sulfonic acid and mercaptan, and wherein said C
1-5Acyl group, C
1-6Acyl group sulfoamido, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkylamino, C
1-6Alkylsulfonamido, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, aryl sulfonyl, carbamyl imino-, C
2-6Dialkyl amido, heterocyclic radical, heterocyclic radical-carbonyl, heteroaryl, phenoxy and phenyl are replaced by 1 to 5 substituting group that independently is selected from the group that is made up of following group separately according to circumstances: C
1-5Acyl group, C
1-5Acyloxy, C
2-6Thiazolinyl, C
1-4Alkoxyl group, C
1-7Alkyl, C
1-4Alkylamino, C
1-4Alkyl carboxamide groups, C
2-6Alkynyl, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, C
1-4Alkyl urea groups, carbonyl-C
1-6-alkoxyl group, carboxamide groups, carboxyl, cyanic acid, C
3-7Naphthenic base, C
3-7Cycloalkyloxy, C
2-6Dialkyl amido, C
2-6Dialkyl group carboxamide groups, halogen, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, C
1-4Alkylhalide group sulfinyl, C
1-4Alkylhalide group alkylsulfonyl, C
1-4Alkyl halide sulfenyl, heteroaryl, heterocyclic radical, hydroxyl, nitro, phenyl and phosphonato, and wherein said C
1-7Alkyl and C
1-4The alkyl carboxamide groups is selected from by C by 1 to 5 according to circumstances
1-4The substituting group of the group that alkoxyl group and hydroxyl are formed replaces, or R
13Be formula (A) group:
Wherein:
" p " and " r " independently is 0,1,2 or 3, and
And R
18Be H, C
1-5Acyl group, C
2-6Thiazolinyl, C
1-8Alkyl, C
1-4Alkyl carboxamide groups, C
2-6Alkynyl, C
1-4Alkylsulfonamido, carbonyl-C
1-6-alkoxyl group, carboxamide groups, carboxyl, cyanic acid, C
3-7Naphthenic base, C
2-6Dialkyl group carboxamide groups, halogen, heteroaryl or phenyl, and wherein heteroaryl or phenyl independently are selected from by C by 1 to 5 according to circumstances
1-4Alkoxyl group, amino, C
1-4Alkylamino, C
2-6Alkynyl, C
2-8Dialkyl amido, halogen, C
1-4Halogen alkoxyl group, C
1-4The substituting group of the group that alkylhalide group and hydroxyl are formed replaces,
R
14, R
15, R
16, and R
17Independently be selected from the group that forms by following group: H, C separately
1-5Acyl group, C
1-5Acyloxy, C
2-6Thiazolinyl, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkyl carboxamide groups, C
2-6Alkynyl, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, C
1-4Alkyl urea groups, carbonyl-C
1-6-alkoxyl group, carboxamide groups, carboxyl, cyanic acid, C
3-7Naphthenic base, C
2-6Dialkyl group carboxamide groups, halogen, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, C
1-4Alkylhalide group sulfinyl, C
1-4Alkylhalide group alkylsulfonyl, C
1-4Alkyl halide sulfenyl, hydroxyl and nitro; Or
Two adjacent R
14, R
15, R
16And R
17Form and Ar with the atom that is connected with them
1Condensed 5,6 or 7 yuan of naphthenic base, cycloalkenyl group or heterocyclic radicals, wherein said 5,6 or 7 yuan of groups are replaced by halogen according to circumstances, and
R
2Be selected from the group that forms by following group: C
1-8Alkyl, C
2-6Alkynyl, amino, aryl, carboxamide groups, carboxyl, cyanic acid, C
3-6-naphthenic base, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, halogen, heteroaryl and hydroxyl: and wherein said C
1-8Alkyl, aryl or heteroaryl are replaced by 1 to 5 substituting group that is selected from the group that is made up of following group according to circumstances: C
1-5Acyl group, C
1-5Acyloxy, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkylamino, C
1-4Alkyl carboxamide groups, C
1-4Alkylthio carboxamide groups, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, C
1-4Alkylthio urea groups, C
1-4Alkyl urea groups, amino, carbonyl-C
1-6-alkoxyl group, carboxamide groups, carboxyl, cyanic acid, C
3-6-naphthenic base, C
3-6-naphthenic base-C
1-3-assorted alkylidene group, C
2-8Dialkyl amino, C
2-6Dialkyl group carboxamide groups, C
2-6Two alkylthio carboxamide groups, C
2-6Dialkyl group sulfoamido, C
1-4Alkylthio urea groups, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, C
1-4Alkylhalide group sulfinyl, C
1-4Alkylhalide group alkylsulfonyl, C
1-4Alkylhalide group, C
1-4Alkyl halide sulfenyl, halogen, heterocyclic radical, hydroxyl, hydroxyl amino and nitro; Or
R
2For-Ar
2-Ar
3, Ar wherein
2And Ar
3Independent of separately according to circumstances by 1 to 5 substituted aryl of substituting group that is selected from the group that forms by following group or heteroaryl: H, C
1-5Acyl group, C
1-5Acyloxy, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkyl carboxamide groups, C
1-4Alkylthio carboxamide groups, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, amino, C
1-4Alkylamino, carbonyl-C
1-6-alkoxyl group, carboxamide groups, carboxyl, cyanic acid, C
3-6-naphthenic base, C
2-8Dialkyl amido, C
2-6Dialkyl group carboxamide groups, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, halogen, hydroxyl and nitro; Or
R
2Be formula (B) group:
Wherein:
R
19Be H, C
1-8Alkyl, C
3-7Naphthenic base, aryl, heteroaryl or OR
21And R
20Be F, Cl, Br, CN or NR
22R
23R wherein
21Be H, C
1-8Alkyl or C
3-7Naphthenic base, and R
22And R
23Independent separately is H, C
1-8Alkyl, C
3-7Naphthenic base, aryl or heteroaryl;
Or
R
2Be formula (C) group:
Wherein
G is:
1)-C (O)-,-C (O) NR
25-,-NR
25C (O)-,-KR
25-,-NR
25C (O) O-,-OC (O) NR
25-,-CR
25R
26NR
27C (O)-,-CR
25R
26C (O) NR
27-,-C (O) O-,-OC (O)-,-C (S)-,-C (S) NR
25-,-C (S) O-,-OC (S)-,-CR
25R
26-,-O-,-S-,-S (O)-,-S (O)
2-or key, when D is CR
2R
3The time; Or
11)-CR
25R
26C (O)-,-C (O)-,-CR
25R
26C (O) NR
27-,-C (O) NR
25-,-C (O) O-,-C (S)-,-C (S) NR
25-,-C (S) O-,-CR
25R
26-,-S (O)
2Or key, when D is NR
2The time;
R wherein
25, R
26And R
27Independent separately is H or C
1-8Alkyl; And R
24For H, separately according to circumstances by 1 to 5 substituted C of substituting group that is selected from the group that forms by following group
1-8Alkyl, C
3-7Naphthenic base, phenyl, heteroaryl or heterocyclic radical C
1-5Acyl group, C
1-5Acyloxy, C
2-6Thiazolinyl, C
1-4Alkoxyl group, C
1-7Alkyl, C
1-4Alkylamino, C
1-4Alkyl carboxamide groups, C
1-4Alkylthio carboxamide groups, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, C
1-4Alkylthio urea groups, C
1-4Alkyl urea groups, amino, carbonyl-C
1-6-alkoxyl group, carboxamide groups, carboxyl, cyanic acid, C
3-7Naphthenic base, C
2-8Dialkyl amido, C
2-6Dialkyl group carboxamide groups, C
2-6Two alkylthio carboxamide groups, C
2-6Dialkyl group sulfoamido, C
1-4Alkylthio urea groups, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, C
1-4Alkylhalide group sulfinyl, C
1-4Alkylhalide group alkylsulfonyl, C
1-4Alkylhalide group, C
1-4Alkyl halide sulfenyl, halogen, heteroaryl, heterocyclic radical, hydroxyl, hydroxyl amino, nitro, phenyl, phenoxy and sulfonic acid, wherein said C
1-4Alkoxyl group, C
1-7Alkyl, C
1-4Alkylamino, heteroaryl, phenyl and phenoxy are replaced by 1 to 5 substituting group that independently is selected from the group that is made up of following group separately according to circumstances: C
1-5Acyl group, C
1-5Acyloxy, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkylamino, C
1-4Alkyl carboxamide groups, C
1-4Alkylthio carboxamide groups, C
1-6Alkylsulfonamido, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, C
1-4Alkylthio urea groups, C
1-4Alkyl urea groups, amino, carbonyl-C
1-6-alkoxyl group, carboxamide groups, carboxyl, cyanic acid, C
3-7Naphthenic base, C
2-8Dialkyl amido, C
2-6Dialkyl group carboxamide groups, C
2-6Two alkylthio carboxamide groups, C
2-6Dialkyl group sulfoamido, C
1-4Alkylthio urea groups, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, C
1-4Alkylhalide group sulfinyl, C
1-4Alkylhalide group alkylsulfonyl, C
1-4Alkylhalide group, C
1-4Alkyl halide sulfenyl, halogen, heterocyclic radical, hydroxyl, hydroxyl amino, nitro and phenyl, its restricted condition are that Z and U not all are N.
One aspect of the present invention is about medical composition, and it comprises at least a compound of the present invention and pharmaceutically acceptable supporting agent.
One aspect of the present invention is about treating the method for individual metabolic-related disorders, and it comprises to the individuality of the said treatment of needs throws and The compounds of this invention or its medical composition of treating effective dose.
One aspect of the present invention is about reducing the method for individual ingestion of food, and it comprises to the individuality that these needs are arranged throws and The compounds of this invention or its medical composition of treating effective dose.
One aspect of the present invention is about bringing out the method for individual satiety, and it comprises to the individuality that these needs are arranged throws and The compounds of this invention or its medical composition of treating effective dose.
One aspect of the present invention is about control or reduce the method that whose body weight increases, and it comprises to the The compounds of this invention or its medical composition that have the individual throwing of these needs with the treatment effective dose.
One aspect of the present invention is about regulating the method for individual RUP3 acceptor, and it comprises makes said acceptor contact with The compounds of this invention.In certain embodiments, said compound is the RUP3 receptor stimulant.In certain embodiments, the adjusting to the RUP3 acceptor is the treatment metabolic-related disorders.
Some embodiments of the invention comprise a kind of method of regulating individual RUP3 acceptor, and it comprises makes said acceptor contact with The compounds of this invention, and wherein the adjusting to the RUP3 acceptor is to reduce individual ingestion of food.
Some embodiments of the invention comprise a kind of method of regulating individual RUP3 acceptor, and it comprises makes said acceptor contact with The compounds of this invention, and wherein the adjusting to the RUP3 acceptor is to bring out individual satiety.
Some embodiments of the invention comprise a kind of method of regulating individual RUP3 acceptor, and it comprises makes said acceptor contact with The compounds of this invention, and wherein the adjusting to the RUP3 acceptor is control or reduces the whose body weight increase.
Manufacturing is used to treat the purposes of the medicine of metabolic-related disorders to one aspect of the present invention about The compounds of this invention.
Manufacturing is used to reduce the purposes of the medicine of individual ingestion of food to one aspect of the present invention about The compounds of this invention.
Manufacturing is used to bring out the purposes of the medicine of individual satiety to one aspect of the present invention about The compounds of this invention.
Manufacturing is used to control or reduces the purposes of the medicine that whose body weight increases to one aspect of the present invention about The compounds of this invention.
One aspect of the present invention is about being used for the The compounds of this invention through therapy for treating human body or animal body.
One aspect of the present invention is about being used for the The compounds of this invention through therapy for treating human body or animal body metabolic-related disorders.
One aspect of the present invention is about reducing the The compounds of this invention of human body or animal body ingestion of food through therapy.
One aspect of the present invention is about bringing out the The compounds of this invention of human body or animal body satiety through therapy.
One aspect of the present invention is about the The compounds of this invention through therapy control or minimizing human body or animal body weight increase.
Some embodiments of the invention are about 185 to about 45 method about human weight index wherein.In certain embodiments, human weight index is about 25 to about 45.In certain embodiments, human weight index is about 30 to about 45.In certain embodiments, human weight index is about 35 to about 45.
Said in certain embodiments individuality is a Mammals.Said in certain embodiments Mammals is human.
In certain embodiments, said metabolic-related disorders be hyperlipidaemia, type 1 diabetes, diabetes B, specially send out that vascular restenosis after property type 1 diabetes (1b type), the invisible autoimmune diabetes (LADA) of being grown up, early onset diabetes B (EOD), youth's property atypia mellitus (YOAD), young adult morbidity type mellitus (MODY), malnutritive dependency mellitus, gestational diabetes, coronary heart disease, ishemic stroke, the vascular surgery, peripheral vascular disease, intermittent claudication, myocardial infarction (for example necrosis and apoptosis), hyperlipemia, post-prandial lipemia, sugar tolerance impaired (IGT) symptom, the impaired symptom of fasting blood sugar, metabolic acidosis, ketosis, sacroiliitis, obesity, osteoporosis, hypertension, congestive heart failure, left ventricular hypertrophy, peripheral arterial disease, diabetic retinopathy, degeneration of macula, cataract, diabetic nephropathy, glomerulosclerosis, chronic renal failure, diabetic neuropathy, metabolic syndrome, X syndromes, premenstrual syndrome, coronary heart disease, stenocardia, thrombosis, atherosclerosis, myocardial infarction (myocardial infarctoin), TCI, apoplexy, vascular restenosis, hyperglycemia, hyperinsulinemia, hyperlipidaemia, hypertriglyceridemia, insulin resistance, glucose metabolism are bad, the impaired symptom of sugar tolerance, the impaired symptom of fasting blood sugar, obesity, erective dysfunction, skin and reticular tissue illness, pedopathy and ulcerative colitis, endothelial function is unusual and the blood vessel compliance is impaired.
In certain embodiments, said metabolic-related disorders is type i diabetes, type ii diabetes, improper glucose tolerance, insulin resistance, hyperglycemia, hyperlipidaemia, hypertriglyceridemia, hypercholesterolemia, hyperlipemia or X syndromes.In certain embodiments, said metabolic-related disorders is a type ii diabetes.In certain embodiments, said metabolic-related disorders is a hyperglycemia.In certain embodiments, said metabolic-related disorders is a hyperlipidaemia.In certain embodiments, said metabolic-related disorders is a hypertriglyceridemia.In certain embodiments, said metabolic-related disorders is a type i diabetes.In certain embodiments, said metabolic-related disorders is a hyperlipemia.In certain embodiments, said metabolic-related disorders is the X syndromes.
One aspect of the present invention is about a kind of method for preparing medical composition, and it comprises at least a compound as herein described is mixed with pharmaceutically acceptable supporting agent.
The application's case be with the U.S. Provisional Patent Application case sequence number 60/487,443 of on July 14th, 2003 application and submission on October 10th, 2003 60/510,644 both are relevant, the both is incorporated herein by reference fully.
Application case keeps the right of any or more than one compounds of getting rid of any embodiment of the invention.Application case keeps the right of any disease, symptom or the illness of getting rid of any embodiment of the invention in addition.
Description of drawings
Figure 1A is showed in the RT-PCR that expresses RUP3 in the human tissue and analyzes.22 human tissues have been analyzed altogether.
Figure 1B shows the cDNA Dot blot analysis that RUP3 expresses in human tissue.
Fig. 1 C shows that with human youth's lattice Han Shi (Langerhans) pancreas islet that exsomatizes RUP3 being carried out RT-PCR analyzes.
Fig. 1 D shows that the RT-PCR that RUP3 expresses analyzes in the cDNA of rat source.
Fig. 2 A shows that the many strains that produce in the rabbit resist-RUP3 antibody.
Fig. 2 B shows the expression of RUP3 in the beta Cell of islet that produces Regular Insulin.
Fig. 3 shows in vitro functionally active of RUP3.
Fig. 4 shows the RUP3RNA trace.
Embodiment
Scientific literature around the acceptor development has taked many terms to refer to acceptor is had the part of various effects.With consistent, patent document will be used to give a definition in full for clear.
Agonist means acceptor interaction and the activated receptor with for example RUP3 acceptor, and causes the part of acceptor physiology or pharmacology response characteristic.For example, in the cell when said part activates with receptors bind when response or enhancing and membrane-bound GTP.
Amino acid abbreviations used herein is listed in table 1:
Table 1
| L-Ala | ?ALA | A |
| L-arginine | ?ARG | R |
| L-asparagine | ?ASN | N |
| Aspartic acid | ?ASP | D |
| Halfcystine | ?CYS | C |
| L-glutamic acid | ?GLU | E |
| Stimulina | ?GLN | Q |
| Glycocoll | ?GLY | G |
| Histidine | ?HIS | H |
| Isoleucine | ?ILE | I |
| Leucine | ?LEU | L |
| Methionin | ?LYS | K |
| Methionine(Met) | ?MET | M |
| Phenylalanine(Phe) | ?PHE | F |
| Proline(Pro) | ?PRO | P |
| Serine | ?SER | S |
| Threonine | ?THR | T |
| Tryptophane | ?TRP | W |
| Tyrosine | ?TYR | Y |
| Xie Ansuan | ?VAL | V |
| L-Ala | ?ALA | A |
The term antagonist should refer in position identical with agonist and receptor competition bonded part (for example endogenic ligand); But it does not activate in the cell that is caused by the receptor active form and responds, and therefore can suppress the interior response of cell of agonist or partial agonist.Antagonist can not reduce to respond in the baseline cell when not having agonist or partial agonist.
Chemical based, part or group:
Term " C
1-5Acyl group " C that links to each other with carbonyl of expression
1-5Alkyl is wherein identical with definition described herein to the definition of alkyl; Some instances include, but is not limited to ethanoyl, propionyl group, positive butyryl radicals, isobutyryl, secondary butyryl radicals, uncle's butyryl radicals (meaning is a valeryl), pentanoyl etc.
Term " C
1-5Acyloxy " acyl group that links to each other with a Sauerstoffatom of expression, wherein acyl group has and identical definition described herein; Some instances include, but is not limited to acetoxyl group, propionyloxy, butyryl acyloxy, isobutyl acyloxy, secondary butyryl acyloxy, uncle's butyryl acyloxy etc.
Term " C
1-6The acyl group sulfoamido " refer to the C that directly links to each other with the nitrogen of sulfoamido
1-6Acyl group, wherein C
1-6Acyl group has and identical definition described herein with sulfoamido, and C
1-6The acyl group sulfoamido can be expressed from the next:
Some embodiments of the invention are to be C at the acyl group sulfoamido
1-5During the acyl group sulfoamido, some embodiment are C
1-4Acyl group sulfoamido, some embodiment are C
1-3The acyl group sulfoamido, and some embodiment are C
1-2The acyl group sulfoamido.The instance of acyl group sulfoamido include, but is not limited to the ethanoyl sulfamyl [S (=O)
2NHC (=O) Me], the propionyl group sulfamyl [S (=O)
2NHC (=O) Et], isobutyryl sulfamyl, butyryl radicals sulfamyl, 2-methyl-butyryl radicals sulfamyl, 3-methyl-butyryl radicals sulfamyl, 2,2-dimethyl--propionyl group sulfamyl, pentanoyl sulfamyl, 2-methyl-pentanoyl sulfamyl, 3-methyl-pentanoyl sulfamyl, 4-methyl-pentanoyl sulfamyl etc.
Term " C
2-6Thiazolinyl " expression contains the group of 2 to 6 carbon atoms, wherein has at least one carbon-to-carbon double bond, and some embodiment are 2 to 4 carbon atoms, and some embodiment are 2 to 3 carbon atoms, and some embodiment have 2 carbon atoms.E and Z isomer all are contained in the term " thiazolinyl ".In addition, term " thiazolinyl " comprises dialkylene and trialkenyl.Therefore, two so said keys of key can all be the mixture of E or Z or E and Z more than one if exist.The instance of thiazolinyl comprises vinyl, allyl group, crotyl, 3-crotonyl, pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2,4-hexadienyl etc.
Term " C used herein
1-4Alkoxyl group " represent to define the alkyl that directly is connected with Sauerstoffatom like this paper.Instance comprises methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, tert.-butoxy, isobutoxy, sec.-butoxy etc.
Term " C
1-8Alkyl " expression contains the straight or branched carbon back of 1 to 8 carbon atom, and some embodiment are 1 to 6 carbon atom, and some embodiment are that 1 to 3 carbon atom and some embodiment are 1 or 2 carbon atom.Examples of alkyl includes, but is not limited to methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec.-butyl, isobutyl-, the tertiary butyl, amyl group, isopentyl, tert-pentyl, neo-pentyl, [meaning is-CH (CH the 1-methylbutyl
3) CH
2CH
2CH
3], the 2-methylbutyl [meaning promptly-CH
2CH (CH
3) CH
2CH
3], n-hexyl etc.
Term " C
1-4The alkyl carboxamide groups " (" C
1-4Alkylcarboxamido " or " C
1-4Alkylcarboxamide ") the independent C that links to each other with the nitrogen of acid amides of expression
1-4Alkyl, wherein alkyl has and identical definition described herein.Said C
1-5The alkyl carboxamide groups can be by following expression:
Instance includes, but is not limited to N-methyl carboxamide groups, N-ethyl carboxamide groups, N-n-propyl carboxamide groups, N-sec.-propyl carboxamide groups, N-normal-butyl carboxamide groups, N-sec.-butyl carboxamide groups, N-isobutyl-carboxamide groups, N-tertiary butyl carboxamide groups etc.
Term " C
1-3Alkylidene group " be meant C
1-3Divalence straight chain carbon back.C in certain embodiments
1-3Alkylidene group for example is meant-CH
2-,-CH
2CH
2-,-CH
2CH
2CH
2-etc.
C in certain embodiments
1-3Alkylidene group is meant-CH-,-CHCH
2-,-CHCH
2CH
2-etc., wherein said instance relates generally to " A ".
Term " C
1-4Alkyl sulphinyl " expression and formula-S (O)-the C that is connected of sulfoxide group
1-4Alkyl, wherein said alkyl have and identical definition described herein.Instance includes, but is not limited to methylsulfinyl, ethyl sulfinyl, n-propyl sulfinyl, sec.-propyl sulfinyl, normal-butyl sulfinyl, sec.-butyl sulfinyl, isobutyl-sulfinyl, the tertiary butyl etc.
Term " C
1-4Alkylsulfonamido " be meant following groups
C wherein
1-4Alkyl has and identical definition described herein.
Term " C
1-4Alkyl sulphonyl " expression and formula-S (O)
2-the C that connects of sulfuryl
1-4Alkyl, wherein said alkyl have and identical definition described herein.Instance includes, but is not limited to methyl sulphonyl, ethylsulfonyl, n-propyl alkylsulfonyl, sec.-propyl alkylsulfonyl, normal-butyl alkylsulfonyl, sec.-butyl alkylsulfonyl, isobutyl-alkylsulfonyl, the tertiary butyl etc.
Term " C
1-4Alkylthio " C that is connected with the sulfenyl of formula-S-of expression
1-4Alkyl, wherein said alkyl have and identical definition described herein.Instance includes, but is not limited to the methyl sulfenyl, and (meaning is CH
3S-), ethyl sulfenyl, n-propyl sulfenyl, sec.-propyl sulfenyl, normal-butyl sulfenyl, sec.-butyl sulfenyl, isobutyl-sulfenyl, the tertiary butyl etc.
Term " C
1-4The alkylthio carboxamide groups " expression following formula thioamides
C wherein
1-4Alkyl has and identical definition described herein.
Term " C
1-4The alkylthio urea groups " group of expression-NC (S) N-, wherein two nitrogen-atoms are all by identical or different C
1-4Alkyl replaces and alkyl has and identical definition described herein.The instance of alkylthio urea groups includes, but is not limited to: CH
3NHC (S) NH-, NH
2C (S) NCH
3-, (CH
3)
2N (S) NH-, (CH
3)
2N (S) NH-, (CH
3)
2N (S) NCH
3-, CH
3CH
2NHC (S) NH-, CH
3CH
2NHC (S) NCH
3-etc.
Term " C
1-4The alkyl urea groups " group of expression-NC (O) N-, wherein two nitrogen-atoms are all by identical or different C
1-4Alkyl replaces and alkyl has and identical definition described herein.The instance of alkyl urea groups includes, but is not limited to: CH
3NHC (O) NH-, NH
2C (O) NCH
3-, (CH
3)
2N (O) NH-, (CH
3)
2N (O) NH-, (CH
3)
2N (O) NCH
3-, CH
3CH
2NHC (O) NH-, CH
3CH
2NHC (O) NCH
3-etc.
Term " C
2-6Alkynyl " expression contains the group of 2 to 6 carbon atoms and at least one carbon-to-carbon triple bond, and some embodiment are 2 to 4 carbon atoms, and some embodiment are 2 to 3 carbon atoms, and some embodiment have 2 carbon atoms.The instance of alkynyl includes, but is not limited to ethynyl, 1-proyl, 2-propynyl, ethyl acetylene base, 2-butyne base, 3-butynyl, 1-pentynyl, valerylene base, 3-pentynyl, 4-pentynyl, 1-hexyn, 2-hexyn, 3-hexyn, 4-hexyn, 5-hexyn etc.Term " alkynyl " comprises diine and three alkynes.
Term " amino " expression group-NH
2
Term " C
1-4Alkylamino " alkyl that is connected with amino of expression, wherein said alkyl has and identical definition described herein.Some instances include, but is not limited to that methylamino-, ethylamino, n-propylamine base, isopropylamino, n-butyl amine base, Zhong Ding are amino, isobutyl is amino, uncle's fourth amino etc.Some embodiment are " C
1-2Alkylamino ".
Term " aryl " expression contains the fragrant cyclic group of 6 to 10 ring carbon atoms.Instance comprises phenyl and naphthyl.
Term " aralkyl " for example defines-CH
2-,-CH
2CH
2-the C that waits
1-C
4Alkylidene group, it is further replaced by aryl again.The instance of " aralkyl " comprises benzyl, styryl (phenethylene) etc.
Single aryl that term " aryl carboxamide groups " expression is connected with the nitrogen of carboxamido-group, wherein aryl has and identical definition described herein.Instance is a N-phenyl carboxamide base.
Term " aryl-ureido " expression group-NC (O) N-, one of them nitrogen is replaced by an aryl.
Term " benzyl " expression group-CH
2C
6H
5
Term " carbonyl-C
1-6-alkoxyl group " be meant the C of carboxylic acid
1-6Alkyl ester, wherein said alkyl has definition as herein described.In certain embodiments, carbonyl-C
1-6-alkoxyl group is connected with nitrogen-atoms and forms carbamate groups (N-COO-C for example jointly
1-6-alkyl).In certain embodiments, carbonyl-C
1-6-alkoxyl group be ester (for example-COO-C
1-6-alkyl).Instance includes, but is not limited to methoxycarbonyl, ethoxycarbonyl, the third oxygen carbonyl, the different third oxygen carbonyl, butoxy carbonyl, secondary butoxy carbonyl, isobutyl boc, tertbutyloxycarbonyl, positive penta oxygen carbonyl, isoamyl oxygen carbonyl, uncle's penta oxygen carbonyl, new penta oxygen carbonyl, just own oxygen carbonyl etc.
Term " carboxamide groups " is meant group-CONH
2
Term " carboxyl " (" carboxy " or " carboxyl ") expression group-CO
2H; Be also referred to as the carboxylic acid group.
Term " cyanic acid " expression group-CN.
Term " C
3-7Cycloalkenyl group " expression contains the non-aromatic ring base of 3 to 6 ring carbon atoms and at least one two key, and some embodiment contain 3 to 5 carbon atoms; Some embodiment contain 3 to 4 carbon atoms.Instance comprises: cyclopropenyl radical, cyclobutene base, cyclopentenyl, cyclopentenyl, cyclohexenyl etc.
Term " C
3-7Naphthenic base " expression contains the saturated cyclic group of 3 to 6 carbon atoms; Some embodiment contain 3 to 5 carbon atoms; Some embodiment contain 3 to 4 carbon atoms.Instance comprises: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentyl, cyclohexyl, suberyl etc.
Term " C
4-8The diamide base " amino of expression and the acyl group keyed jointing of two this paper definition, wherein said acyl group can be identical or different, for example:
C
4-8The instance of diamide base includes, but is not limited to diacetylamino, dipropyl acidamide base, acetyl-propionyl amido etc.
Term " C
2-6Dialkyl amido " expression is by two substituted amino of identical or different alkyl, and wherein alkyl has and identical definition described herein.Some instances include, but is not limited to that dimethylamino, methyl ethylamino, diethylin, methyl-prop are amino, methyl isopropyl is amino, ethyl third amino, ethyl isopropylamino, dipropyl amino, propyl group isopropylamino etc.Some embodiment are " C
2-4Dialkyl amido ".
Term " C
1-4The dialkyl group carboxamide groups " two identical or different alkyl being connected with a carboxamido-group of (" dialkylcarboxamido " or " dialkylcarboxamide ") expression, wherein alkyl has and identical definition described herein.C
1-4The dialkyl group carboxamide groups can be represented by following groups:
C wherein
1-4Have and identical definition described herein.The instance of dialkyl group carboxamide groups includes, but is not limited to N, N-dimethyl-carboxamide groups, N-methyl-N-ethyl carboxamide groups, N, N-diethylammonium carboxamide groups, N-methyl-N-isopropyl propyl group carboxamide groups etc.
Term " C
2-6The dialkyl group sulfoamido " be meant following shown in one of group:
Term " C
2-6Two alkylthio carboxamide groups " (" dialkylthiocarboxamido " or " C
2-6Dialkylthiocarboxamide ") two identical or different alkyl being connected with the monothio carboxamido-group of expression, wherein alkyl has and identical definition described herein.C
1-4Two alkylthio carboxamide groups can be represented by following groups:
The instance of
two alkylthio carboxamide groups includes, but is not limited to N, N-methyl-sulfide yl-carboxamides base, N-methyl-N-ethylmercapto group carboxamide groups etc.
Term " C
2-6The dialkyl group sulfoamido " be meant and as two C defined herein
1-3The amino of alkyl sulphonyl keyed jointing.
Term " ethynylene " is meant carbon-to-carbon triple bond base as follows:
Term " formyl radical " is meant group-CHO.
Term " C
1-4The halogen alkoxyl group " expression as alkylhalide group defined herein, it directly is connected with a Sauerstoffatom.Instance includes, but is not limited to difluoro-methoxy, trifluoromethoxy, 2,2,2-trifluoro ethoxy, five fluorine oxyethyl groups etc.
Term " C
1-4Alkylhalide group " expression as C defined herein
1-4Alkyl, wherein said alkyl is replaced up to being substituted fully by a kind of halogen, and complete substituted C
1-4Alkylhalide group can be by formula C
nL
2n+1Expression, wherein L is that halogen and " n " they are 1,2,3 or 4; They can be identical or different and be selected from the group that is made up of F, Cl, Br and I when having more than one halogens, are preferably F.C
1-4The alkylhalide group instance includes, but is not limited to methyl fluoride, difluoromethyl, trifluoromethyl, chlorodifluoramethyl-, 2,2,2-trifluoroethyl, pentafluoroethyl group etc.
Term " C
1-4The alkylhalide group carboxamide groups " expression alkyl carboxamide groups defined herein, wherein said alkyl is replaced up to being substituted fully by a kind of halogen, and complete substituted alkyl is by formula C
nL
2n+1Expression, wherein L is that halogen and " n " are 1,2,3 or 4.They can be identical or different and be selected from the group that is made up of F, Cl, Br and I when having more than one halogens, are preferably F.
Term " C
1-4The alkylhalide group sulfinyl " expression and formula-S (O)-the alkylhalide group that is connected of sulfoxide group, wherein said alkylhalide group has and identical definition described herein.Instance includes, but is not limited to trifluoromethyl sulphinyl base, 2,2,2-trifluoroethyl sulfinyl, 2,2-two fluoro ethyl sulfinyls etc.
Term " C
1-4The alkylhalide group alkylsulfonyl " expression and formula-S (O)
2-the alkylhalide group that connects of sulfuryl, wherein alkylhalide group has and identical definition described herein.Instance includes, but is not limited to trifluoromethyl sulfonyl, 2,2,2-trifluoroethyl alkylsulfonyl, 2,2-difluoro ethylsulfonyl etc.
Term " C
1-4The alkyl halide sulfenyl " the direct alkylhalide group that links to each other with sulphur of expression, wherein alkylhalide group has and identical meaning described herein.Instance includes, but is not limited to trifluoromethylthio, and (meaning is CF
3S-), 1,1-difluoro ethylmercapto group, 2,2,2-trifluoro ethylmercapto group etc.
Term " halogen " (" halogen " or " halo ") expression fluorine, chlorine, bromine or iodine base.
Term " C
1-2Assorted alkylidene group " be meant with one be selected from O, S, S (O), S (O)
2C with the heteroatoms keyed jointing of NH
1-2Alkylidene group.Some representative example include, but is not limited to the following formula group:
Term " heteroaryl " expression aromatic nucleus system, said aromatic nucleus system can be heteroatoms metathetical monocycle, two condensed ring or three condensed ring of the group that selected free O, S and the N of at least one ring carbon atom wherein formed, and wherein N can be according to circumstances by H, C
1-4Acyl group or C
1-4Alkyl replaces.The instance of heteroaryl includes, but is not limited to pyridyl, benzofuryl, pyrazinyl, pyridazinyl, pyrimidyl, triazinyl, quinoline, benzoxazole, benzothiazole, 1H-benzoglyoxaline, isoquinoline 99.9, quinazoline, quinoxaline etc.In certain embodiments, the heteroaryl atom is O, S, NH, and instance includes, but is not limited to pyrroles, indoles etc.Other instance include, but is not limited to those in table 2A, table 4 etc.
Term " heterocyclic radical " expression non-aromatic carbocyclic ring (being naphthenic base or cycloalkenyl group defined herein); One of them, two or three ring carbon atoms are selected from (but being not limited to) heteroatoms displacement by the group that O, S, N formed, wherein N can be according to circumstances by H, C
1-4Acyl group or C
1-4Alkyl replaces, and therefore ring carbon atom is formed carbonyl or thiocarbonyl by ketone group or the replacement of sulfo-ketone group according to circumstances.Heterocyclic radical is the ring that contains 3-, 4-, 5-, 6-or 7-unit.The heterocyclic radical instance includes, but is not limited to ethylene imine-1-base, ethylene imine-2-base, azetidine-1-base, azetidine-2-base, azetidine-3-base, piperidines-1-base, piperidin-4-yl, morpholine-4-base, piperazine-1-base, piperazine-4-base, tetramethyleneimine-1-base, tetramethyleneimine-3-base, [1,3]-dioxolane-2-base etc.Other examples show of heterocyclic radical is in hereinafter table 2B, 2C, 2D, 2E, 2F and 2G.
The heterocyclic radical as this paper defines directly and the carbon bond of carbonyl (being C=O) connects represented in term " heterocyclic radical-carbonyl ".In certain embodiments, the theheterocyclic nitrogen atom of heterocyclic radical can be bonded to carbonyl and form acid amides.Instance includes, but is not limited to,
In certain embodiments, ring carbon atom is bonded to carbonyl and forms ketone group.Instance includes, but is not limited to,
Term " heterocyclic radical-oxygen base " is meant like this paper and defines directly and the heterocyclic radical of Sauerstoffatom keyed jointing.Instance comprises following:
Term " heterocyclic carboxamide base " expression defines the heterocyclic radical with theheterocyclic nitrogen atom like this paper, the direct and carbonyl keyed jointing formation carboxamido-group of wherein said theheterocyclic nitrogen atom.Instance includes, but is not limited to,
Term " heterocycle alkylsulfonyl " expression defines the heterocyclic radical with theheterocyclic nitrogen atom like this paper, the direct and SO of wherein said theheterocyclic nitrogen atom
2Base key connects the formation sulfoamido.Instance includes, but is not limited to
Term " hydroxyl " is meant group-OH.
Term " hydroxylamino " is meant group-NHOH.
Term " nitro " is meant group-NO
2
Term " C
4-7Ketone group-naphthenic base " be meant C like this paper definition
4-7Naphthenic base, one of them ring carbon atom is replaced by carbonyl.C
4-7The instance of ketone group-naphthenic base includes, but is not limited to 2-ketone group-cyclobutyl, 3-ketone group-cyclobutyl, 3-ketone group-cyclopentyl, 4-ketone group-cyclohexyl etc. and is represented by following structure respectively:
Term " perfluoroalkyl " expression-C
nF
2n+1Group; In other words, perfluoroalkyl is an alkyl of deciding literary composition like this paper, and wherein said alkyl is replaced by fluorine atom fully and therefore thinks that it is the subclass of alkylhalide group.The instance of perfluoroalkyl comprises CF
3, CF
2CF
3, CF
2CF
2CF
3, CF (CF
3)
2, CF
2CF
2CF
2CF
3, CF
2CF (CF
3)
2, CF (CF
3) CF
2CF
3Deng.
Term " phenoxy " is meant group C
6H
5O-.
Term " phenyl " is meant group C
6H
5-.
Term " phosphonato " is meant the group with following chemical structure:
Term " sulfoamido " is meant group-SO
2NH
2
Term " sulfonic acid " is meant group-SO
3H.
Term " tetrazyl " is meant the quinary heteroaryl of following formula:
In certain embodiments, said tetrazyl selected free C on 1 or 5 respectively again
1-3Alkyl, C
1-3Alkylhalide group and C
1-3The group of the group that alkoxyl group is formed replaces.
Term " mercaptan " expression group-SH.
Codon should refer to the aggregate of three Nucleotide (or nucleotide equivs), comprises nucleosides (adenosine (A), guanosine-(G), cytidine(C (C), uridine (U) and Thymine deoxyriboside (T)) and its coded amino acid when translating with phosphate-based coupling as the one of which.
Compsn should refer to comprise the material of at least two kinds of compounds or two kinds of components; For example (unrestriction) medical composition is a kind of compsn that comprises The compounds of this invention and pharmaceutically acceptable supporting agent.
Compound is renderd a service and should be referred to and receptors bind avidity opposite (as opposed to), and compound suppresses or excites function of receptors performance force measurement.
Activated receptors should refer to stand the acceptor of structure receptor activation on the structure.
The structure receptor activation should refer to make acceptor stable in active condition through except with acceptor and mode its endogenic ligand or its chemical equivalence thing combine.
Contact (" CONTACT " or " CONTACTING ") should instigate indicated segment set to lump together, regardless of system in vitro still in vivo in the system.Therefore RUP3 acceptor and The compounds of this invention " are contacted " and comprise the individuality of The compounds of this invention being thrown and having the RUP3 acceptor, preferably human, and for example The compounds of this invention introducing one is contained the preparation that cell sample or contains the more purifying of RUP3 acceptor.
Endogenous should refer to the material of the natural generation of Mammals.Endogenous should refer to Mammals (for example (but being not limited to) mankind) or viral natural generation when being related to (for example (but being not limited to)) term " acceptor ".
On the contrary, the non-endogenous of term should refer to not to be Mammals (for example (but being not limited to) mankind) or viral natural generation among this paper.For example (non-limiting), the structure sensitization but after operation, become the active acceptor of the structure of signing an undertaking and most preferably be called " non-endogenous, structure activated receptor " in this article of not signing an undertaking in the form of source within it.Two terms may be used to describe " in vivo " and " in vitro " system.For example (non-limiting), in sieve method, endogenous or non-endogenous receptor can be related to a screening system in vitro.As another instance (non-limiting), when mammiferous genome being processed into when comprising non-endogenous structure activated receptor, be feasible through screening system one candidate compound in vivo.
Needs prevention used herein or treatment refer to monitoring person and (for example with regard to human, are doctor, nurse, nurse practitioner etc.; With regard to comprising the animal of non-human mammal, be the animal doctor) judgement made: an individuality or animal need prevent or treat maybe will have benefited from prevention or treatment.This judgement is based on that various factors in monitoring person's professional technique category makes, but it comprises and knows said individuality or animal because of the medicable disease of compound of the present invention, symptom or illness is ill or will be ill.Generally speaking, " need prevention " be meant that individuality that monitoring person makes is with ill judgement.In this background, compound of the present invention is to use with protection or precautionary approach.Be meant the ill judgement of individuality that monitoring person makes yet " need treatment ", therefore use compound of the present invention to alleviate, suppress or improve disease, symptom or illness.
Individuality used herein is meant any animal that comprises Mammals, is preferably mouse, rat, other rodent, rabbit, dog, cat, pig, ox, sheep, horse or primates, and most preferably is the mankind.
Suppress to refer to when (INHIBIT or INHIBITING) is related to term " response " and not exist compound opposite, when having this compound, reduce or the prevention response.
Inverse agonist should refer to combine with the endogenous form of acceptor or with the structure activated form bonded part of acceptor; And said part suppresses response in the baseline cell that activity form caused of acceptor to such an extent that be lower than the active normal datum-plane that under the situation that does not have agonist or partial agonist, is observed, or reduces combining of GTP and cytolemma.Preferred situation does, the benchmark response when not having inverse agonist is compared, and response is suppressed at least 30%, more preferably at least 50% in the said benchmark cell when having inverse agonist, and most preferably at least 75%.
Part should refer to be specific to the natural generation molecule of endogenous of the natural generation acceptor of (specffic for) endogenous.
Quantity, quality, response or the effect that (MODULATE or MODULATING) should refer to increase or reduce given activity, function or molecule regulated in term used herein.
Medical composition should refer to comprise the compsn of at least a active ingredient, and said thus compsn can be stood the given efficacy outcome research of Mammals (such as but not limited to the mankind).One skilled in the art will understand and recognize and be suitable for confirming that whether a kind of active ingredient has the technology of the efficacy outcomes of wanting according to technician's needs.
Treatment effective dose used herein is meant the amount of active compound or medicament; The amount of said active compound or medicament can cause biological response or the medicine response that researcher, animal doctor, the doctor of medicine or other clinician seek in tissue, system, animal, individuality or the mankind, it comprises one or more following persons:
(1) preventing disease; For example prevent individual disease, symptom or illness, the said disease of said individual easy infection, symptom or illness but still do not experience or show the pathology or the symptom of said disease,
(2) suppress disease, for example suppress individual disease, symptom or illness, said individual experience or show said disease, symptom or illness pathology or symptom (that is, stoping further developing of pathology and/or symptom) and
(3) improve disease, for example improve individual disease, symptom or illness, said individual pathology or the symptom (that is, making pathology and/or symptom alteration) that experiences or show said disease, symptom or illness.
The compounds of this invention:
One aspect of the present invention contains fused-aryl and heteroaryl derivative shown in the formula (I):
Or its pharmaceutically acceptable salt, hydrate or solvolyte, wherein Ar
1, M, T, J, Y, X, V, W, Z, U, Q, K, E, A, B, D and
Have and this paper, preceding text and hereinafter described identical definition.
Some embodiments of the invention contain fused-aryl and heteroaryl derivative shown in the formula (I):
A and B are separately independently for being selected from by C by 1 to 4 according to circumstances
1-3Alkyl, C
1-4Alkoxyl group, carboxyl, cyanic acid, C
1-3The substituted C of substituting group of the group that alkylhalide group and halogen are formed
1-3Alkylidene group;
D is O, S, S (O), S (O)
2, CR
1R
2Or N-R
2, R wherein
1Be selected from by H, C
1-8Alkyl, C
1-4The group that alkoxyl group, halogen and hydroxyl are formed;
E is N, C or CR
3, R wherein
3Be H or C
1-8Alkyl;
When E is N or CR
3The time
Be singly-bound, or when E is C
Be two keys;
K is for be selected from by C by 1 to 4 according to circumstances
1-3Alkyl, C
1-4Alkoxyl group, carboxyl, cyanic acid, C
1-3The substituted C of substituting group of the group that alkylhalide group and halogen are formed
1-3Alkylidene group, or K is key,
Q is NR
4, O, S, S (O) or S (O)
2, R wherein
4Be H or C
1-8Alkyl;
T is N or CR
5,
M is N or CR
6
J is N or CR
7
U is C or N;
V is N, CR
8Or V is a key:
W is N or C;
X is O, S, N, CR
9Or NR
11
Y is O, S, N, CR
10Or NR
12
Z is C or N,
R
5, R
6, R
7, R
8, R
9And R
10Independently be selected from the group that forms by following group: H, C
1-5Acyloxy, C
2-6Thiazolinyl, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkyl carboxamide groups, C
2-6Alkynyl, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, C
1-4Alkyl urea groups, amino, C
1-4Alkylamino, C
2-8Dialkyl amido, carboxamide groups, cyanic acid, C
3-6Naphthenic base, C
2-6Dialkyl group carboxamide groups, C
2-6Dialkyl group sulfoamido, halogen, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, C
1-4Alkylhalide group sulfinyl, C
1-4Alkylhalide group alkylsulfonyl, C
1-4Alkyl halide sulfenyl, hydroxyl, hydroxyl amino and nitro, wherein said C
2-6Thiazolinyl, C
1-8Alkyl, C
2-6Alkynyl and C
3-6Naphthenic base is replaced by 1,2,3 or 4 substituting group that is selected from the group that is made up of following group according to circumstances: C
1-5Acyl group, C
1-5Acyloxy, C
1-4Alkoxyl group, C
1-4Alkylamino, C
1-4Alkyl carboxamide groups, C
1-4Alkylthio carboxamide groups, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, C
1-4Alkylthio urea groups, C
1-4Alkyl urea groups, amino, carbonyl-C
1-6-alkoxyl group, carboxamide groups, carboxyl, cyanic acid, C
2-8Dialkyl amido, C
2-6Dialkyl group carboxamide groups, C
1-4Two alkylthio carboxamide groups, C
2-6Dialkyl group sulfoamido, C
1-4Alkylthio urea groups, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, C
1-4Alkylhalide group sulfinyl, C
1-4Alkylhalide group alkylsulfonyl, C
1-4Alkylhalide group, C
1-4Alkyl halide sulfenyl, halogen, hydroxyl, hydroxyl amino and nitro:
R
11And R
12Independently be selected from according to circumstances by 1,2,3 or 4 substituted C of substituting group that is selected from the group that forms by following group
2-6Thiazolinyl, C
1-8Alkyl, C
2-6Alkynyl or C
3-6Naphthenic base: C
1-5Acyl group, C
1-5Acyloxy, C
1-4Alkoxyl group, C
1-4Alkylamino, C
1-4Alkyl carboxamide groups, C
1-4Alkylthio carboxamide groups, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, C
1-4Alkylthio urea groups, C
1-4Alkyl urea groups, amino, carbonyl-C
1-6-alkoxyl group, carboxamide groups, carboxyl, cyanic acid, C
2-8Dialkyl amido, C
2-6Dialkyl group carboxamide groups, C
1-4Two alkylthio carboxamide groups, C
2-6Dialkyl group sulfoamido, C
1-4Alkylthio urea groups, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, C
1-4Alkylhalide group sulfinyl, C
1-4Alkylhalide group alkylsulfonyl, C
1-4Alkylhalide group, C
1-4Alkyl halide sulfenyl, halogen, hydroxyl, hydroxyl amino and nitro;
Ar
1For separately according to circumstances by R
13, R
14, R
15, R
16And R
17Substituted aryl or heteroaryl; R wherein
13Be selected from the group that forms by following group: H, C
1-5Acyl group, C
1-5Acyloxy, C
2-6Thiazolinyl, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkyl carboxamide groups, C
2-6Alkynyl, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, C
1-4Alkyl urea groups, amino, aryl sulfonyl, carbonyl-C
1-6-alkoxyl group, carboxamide groups, carboxyl, cyanic acid, C
3-7Naphthenic base, C
2-6Dialkyl group carboxamide groups, halogen, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, C
1-4Alkylhalide group sulfinyl, C
1-4Alkylhalide group alkylsulfonyl, C
1-4Alkyl halide sulfenyl, heterocyclic radical, heterocycle alkylsulfonyl, heteroaryl, hydroxyl, nitro, C
4-7Ketone group-naphthenic base, phenoxy, phenyl, sulfoamido and sulfonic acid, and wherein said C
1-5Acyl group, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkylsulfonamido, alkyl sulphonyl, aryl sulfonyl, heteroaryl, phenoxy or phenyl are replaced by 1 to 5 substituting group that independently is selected from the group that is made up of following group separately according to circumstances: C
1-5Acyl group, C
1-5Acyloxy, C
2-6Thiazolinyl, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkyl carboxamide groups, C
2-6Alkynyl, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, C
1-4Alkyl urea groups, carbonyl-C
1-6-alkoxyl group, carboxamide groups, carboxyl, cyanic acid, C
3-7Naphthenic base, C
2-6Dialkyl group carboxamide groups, halogen, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, C
1-4Alkylhalide group sulfinyl, C
1-4Alkylhalide group alkylsulfonyl, C
1-4Alkyl halide sulfenyl, heteroaryl, heterocyclic radical, hydroxyl, nitro and phenyl; Or
R
13Be formula (A) group:
Wherein:
" p " and " r " independently is 0,1,2 or 3; And
And R
18Be H, C
1-5Acyl group, C
2-6Thiazolinyl, C
1-8Alkyl, C
1-4Alkyl carboxamide groups, C
2-6Alkynyl, C
1-4Alkylsulfonamido, carbonyl-C
1-6-alkoxyl group, carboxamide groups, carboxyl, cyanic acid, C
3-7Naphthenic base, C
2-6Dialkyl group carboxamide groups, halogen, heteroaryl or phenyl, and wherein heteroaryl or phenyl independently are selected from by C by 1 to 5 according to circumstances
1-4Alkoxyl group, amino, C
1-4Alkylamino, C
2-6Alkynyl, C
2-8Dialkyl amido, halogen, C
1-4Halogen alkoxyl group, C
1-4The substituting group of the group that alkylhalide group and hydroxyl are formed replaces,
R
14-R
17Independently be selected from the H of group, the C that form by following group
1-5Acyl group, C
1-5Acyloxy, C
2-6Thiazolinyl, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkyl carboxamide groups, C
2-6Alkynyl, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, C
1-4Alkyl urea groups, carbonyl-C
1-6-alkoxyl group, carboxamide groups, carboxyl, cyanic acid, C
3-7Naphthenic base, C
2-6Dialkyl group carboxamide groups, halogen, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, C
1-4Alkylhalide group sulfinyl, C
1-4Alkylhalide group alkylsulfonyl, C
1-4Alkyl halide sulfenyl, hydroxyl and nitro; Or
Two adjacent R
14, R
15, R
16And R
17Form and Ar with the atom that is connected with them
1Condensed 5,6 or 7 yuan of naphthenic base, cycloalkenyl group or heterocyclic radicals, wherein said 5,6 or 7 yuan of groups are replaced by halogen according to circumstances, and
R
2Be selected from the group that forms by following group: H, C
1-8Alkyl, C
2-6Alkynyl, amino, aryl, carboxamide groups, carboxyl, cyanic acid, C
3-6-naphthenic base, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, halogen, heteroaryl and hydroxyl; And wherein said C
1-8Alkyl, aryl or heteroaryl are replaced by 1 to 5 substituting group that is selected from the group that is made up of following group separately according to circumstances: C
1-5Acyl group, C
1-5Acyloxy, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkylamino, C
1-4Alkyl carboxamide groups, C
1-4Alkylthio carboxamide groups, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, C
1-4Alkylthio urea groups, C
1-4Alkyl urea groups, amino, carbonyl-C
1-6-alkoxyl group, carboxamide groups, carboxyl, cyanic acid, C
3-6-naphthenic base, C
3-6-naphthenic base-C
1-3-assorted alkylidene group, C
2-8Dialkyl amino, C
2-6Dialkyl group carboxamide groups, C
2-6Two alkylthio carboxamide groups, C
2-6Dialkyl group sulfoamido, C
1-4Alkylthio urea groups, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, C
1-4Alkylhalide group sulfinyl, C
1-4Alkylhalide group alkylsulfonyl, C
1-4Alkylhalide group, C
1-4Alkyl halide sulfenyl, halogen, heterocyclic radical, hydroxyl, hydroxyl amino and nitro, or
R
2For-Ar
2-Ar
3, Ar wherein
2And Ar
3Independent of separately according to circumstances by 1 to 5 substituted aryl of substituting group that is selected from the group that forms by following group or heteroaryl H, C
1-5Acyl group, C
1-5Acyloxy, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkyl carboxamide groups, C
1-4Alkylthio carboxamide groups, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, amino, C
1-4Alkylamino, carbonyl-C
1-6-alkoxyl group, carboxamide groups, carboxyl, cyanic acid, C
3-6-naphthenic base, C
2-8Dialkyl amido, C
2-6Dialkyl group carboxamide groups, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, halogen, hydroxyl and nitro, or
R
2Be formula (B) group:
Wherein
R
19Be H, C
1-8Alkyl, C
3-7Naphthenic base, aryl, heteroaryl or OR
21And R
20Be F, Cl, Br, CN or NR
22R
23R wherein
21Be H, C
1-8Alkyl or C
3-7Naphthenic base, and R
22And R
23Independent is H, C
1-8Alkyl, C
3-7Naphthenic base, aryl or heteroaryl;
Or
R
2Be formula (C) group:
Wherein:
G is selected from the group that is made up of following group:
I) C (O), C (O) NR
25, C (O) O, OC (O), C (S), C (S) NR
25, C (S) O, OC (S), CR
25R
26, O, S, S (O) and when D be CR
1R
2The time be S (O)
2, or
Ii) C (O), C (O) NR
25, C (O) O, C (S), C (S) NR
25, C (S) O, CR
25R
26And when D is NR
2Be S (O)
2,
R wherein
25And R
26Independent is H or C
1-8Alkyl; And
R
24For according to circumstances by 1 to 5 substituted C of substituting group that is selected from the group that forms by following group
1-8Alkyl, C
3-7Naphthenic base, phenyl or heteroaryl: C
1-5Acyl group, C
1-5Acyloxy, C
1-4Alkoxyl group, C
1-7Alkyl, C
1-4Alkylamino, C
1-4Alkyl carboxamide groups, C
1-4Alkylthio carboxamide groups, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, C
1-4Alkylthio urea groups, C
1-4Alkyl urea groups, amino, carbonyl-C
1-6-alkoxyl group, carboxamide groups, carboxyl, cyanic acid, C
3-7Naphthenic base, C
2-8Dialkyl amido, C
2-6Dialkyl group carboxamide groups, C
2-6Dioxane sulphur carboxamide groups, C
2-6Dialkyl group sulfoamido, C
1-4Alkylthio urea groups, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, C
1-4Alkylhalide group sulfinyl, C
1-4Alkylhalide group alkylsulfonyl, C
1-4Alkylhalide group, C
1-4Alkyl halide sulfenyl, halogen, hydroxyl, hydroxyl amino and nitro; Or
Its pharmaceutically acceptable salt, hydrate or solvolyte, its restricted condition are that Z and U not all are N.
Should be appreciated that the present invention for clarity sake is described in special characteristic in the embodiment content separately and also can in an independent embodiment, makes up and provide.On the contrary, the present invention also can separately provide or provide with any suitable son combination for the various characteristics that are described in for purpose of brevity in the independent embodiment content.
At least one Wasserstoffatoms of " being substituted " used herein expression chemical based is by non-hydrogen substituting group or group displacement, and said non-hydrogen substituting group or group can be unit price or divalence.When substituting group or group are divalence, should be appreciated that said group is further replaced by another substituting group or group.When the chemical group of this paper " was substituted ", it can have the metalepsy up to full valence state; For example methyl can be replaced by 1,2 or 3 substituting group, and methylene radical can be replaced by 1 or 2 substituting group, and phenyl can be replaced by 1,2,3,4 or 5 substituting group, and naphthyl can be by 1,2,3,4,5,6 or 7 substituting group replacement etc.Likewise, " replaced " the substituent metalepsy that is meant a group and substituting group a to sum that self is allowed up to said group by one or more substituting groups.In addition, when group was replaced by an above substituting group, they can be identical or different.
Should be appreciated that and understand The compounds of this invention to have one or more chiral centres, and they can be used as enantiomer and/or diastereomer exists.Should understand the present invention and extend to and contain all said enantiomers, diastereomer and its mixture, include, but is not limited to raceme.Therefore, some embodiments of the invention be about such as other used in full chemical formula of formula (I) and this disclosure represented be the compound of R enantiomer.Therefore, some embodiments of the invention be about such as other used in full chemical formula of formula (I) and this disclosure represented be the compound of S enantiomer.In the instance that has an above chiral centre, some embodiments of the invention are included as the compound of RS or SR enantiomer so.In other embodiments, The compounds of this invention is RR or SS enantiomer.Should be appreciated that except as otherwise noted or show, otherwise formula (I) and this disclosure in full the compound of used chemical formula should represent all indivedual enantiomers and its mixture.
The compounds of this invention also can comprise tautomeric form, for example keto-enol tautomerism body etc.Tautomeric form can be in equilibrium state or by being fixed as a kind of form on the suitable metalepsy space.Should be appreciated that various tautomeric forms are in the category of The compounds of this invention.
The compounds of this invention also can comprise all isotope atoms that occur in intermediate compound and/or the final compound.Isotropic substance comprises that those atomicities are identical but atom that total mass number is different.For example, the isotropic substance of hydrogen comprises deuterium and tritium.
In certain embodiments, The compounds of this invention is not 4-[1-(2,4-dimethyl--phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base is amino]-piperidines-1-ethyl formate; 4-(tolyl between 1--1H-pyrazolo [3; 4-d] pyrimidine-4-base is amino)-piperidines-1-ethyl formate, 4-[1-(4-methoxyl group-phenyl)-1H-pyrazolo [3; 4-d] pyrimidine-4-base amino]-piperidines-1-ethyl formate; 4-[1-(4-chloro-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base is amino]-piperidines-1-ethyl formate and 4-(1-phenyl-1H-pyrazolo [3,4-d] pyrimidine-4-base is amino)-piperidines-1-ethyl formate.
In some embodiments of the invention,
is singly-bound.
Some embodiments of the invention are NR about Q wherein
4Compound.In certain embodiments, R
4For according to circumstances by C
2-8The substituted C of dialkyl amido
1-8Alkyl.In certain embodiments, R
4Be selected from the group that is formed by methyl, ethyl, sec.-propyl and 2-dimethylamino-ethyl.In certain embodiments, R
4Be H (meaning is NH).
In certain embodiments, The compounds of this invention can be by formula (Ia) expression of following explanation
Each parameter in its Chinese style (Ia) has this paper, preceding text and implication hereinafter described.
In certain embodiments, K is a key.
In certain embodiments, K is selected from by-CH
2-,-CH
2CH
2-with-CH (CH
3) CH
2-the group that formed.
In certain embodiments, K is-CH
2-or-CH
2CH
2-.
Some embodiments of the invention are the compound of O about Q wherein.Some embodiments of the invention can be by formula (Ic) expression hereinafter described
Each parameter in its Chinese style (Ic) has this paper, preceding text and implication hereinafter described.In certain embodiments, K is-CH
2-or-CH
2CH
2-.
In certain embodiments, The compounds of this invention is expressed as formula (Ic) and K is a key, and said embodiment can be expressed as formula (Id) hereinafter described:
Each parameter in its Chinese style (Id) has this paper, preceding text and implication hereinafter described.
Some embodiments of the invention are S, S (O) or S (O) about Q wherein
2Compound.In certain embodiments, Q is S (O).In certain embodiments, Q is S (O)
2Some embodiments of the invention can be by the formula shown in the hereinafter (Ie), (If) and (Ig) expression.
Its Chinese style (Ie), (If) and (Ig) in each parameter have this paper, preceding text and implication hereinafter described.
Some embodiments of the invention are about compound, and wherein A and B independently are according to circumstances by 1 to 4 substituted C of substituting group that is selected from the group that is made up of following group
1-2Alkylidene group: C
1-3Alkyl, C
1-4Alkoxyl group, carboxyl, cyanic acid, C
1-3Alkylhalide group and halogen.
Some embodiments of the invention about wherein A and B all for according to circumstances by 1 to 2 methyl substituted C
1The compound of alkylidene group.
In certain embodiments, A and B are-CH
2-.Some embodiments of the invention can be expressed as the formula shown in the hereinafter (Ik)
Each parameter in its Chinese style (Ik) has this paper, preceding text and implication hereinafter described.
In certain embodiments, A and B are-CH
2-and E be CH.
In certain embodiments, A and B are-CH
2-, and E is CH, and D is N-R
2
Some embodiments of the invention are about compound, and wherein A is C
1Alkylidene group and B are C
2Alkylidene group, wherein A according to circumstances by 1 to 2 methyl substituted and B according to circumstances by 1 to 4 methyl substituted.In certain embodiments, A is-CH
2-or-CH-and B be-CH
2CH
2-.Should be appreciated that and work as
Have two kinds of methods of describing same ABED loop systems during for singly-bound, for example in certain embodiments, A is-CH
2-, B is-CH
2CH
2-, and for the identical example of executing, A is-CH
2CH
2-and B be-CH
2-, and for identical embodiment, A is-CH
2CH
2-and B be-CH
2-.Therefore, should be appreciated that arbitrary embodiment is correct.Some embodiments of the invention can be represented by formula as follows (Im) with (In) respectively:
Its Chinese style (Im) and (In) in each parameter have this paper, preceding text and implication hereinafter described.In another embodiment, A is-CH
2-, B is-CH
2CH
2-, and K is-CH
2-or-CH
2CH
2-.In certain embodiments, A is-CH
2-, B is-CH
2CH
2-, and K is a key.
In certain embodiments, A is-CH
2CH
2-and B be-CH
2-, and E is CH.
In certain embodiments, A is-CH
2CH
2-and B be-CH
2-, E is that CH and D are N-R
2
Some embodiments of the invention are about compound, and wherein A is C
1Alkylidene group and B are C
3Alkylidene group, wherein A according to circumstances by 1 to 2 methyl substituted and B according to circumstances by 1 to 4 methyl substituted.In certain embodiments, A is-CH
2-or-CH-and B be-CH
2CH
2CH
2-; And can represent by formula as follows (Ip) with (Iq) respectively:
Its Chinese style (Ip) and (Iq) in each parameter have this paper, preceding text and implication hereinafter described.
Some embodiments of the invention are about compound, and wherein A is C
2Alkylidene group and B are C
1Alkylidene group, wherein A according to circumstances by 1 to 4 methyl substituted and B according to circumstances by 1 to 2 methyl substituted.In certain embodiments, A is-CHCH
2-and B be-CH
2-, said embodiment can be represented by formula as follows (It):
Each parameter in its Chinese style (It) has this paper, preceding text and implication hereinafter described.
Some embodiments of the invention are about compound, and wherein A is CH
2And B is-CH
2CH
2-,-CH
2CH (CH
3)-,-CH (CH
3) CH
2-,-CH
2CH (CF
3)-or-CH (CF
3) CH
2-.In certain embodiments, The compounds of this invention is by formula as follows (Iv), (Iw) and (Ix) expression:
Its Chinese style (Iv), (Iw) and (Ix) in each parameter have this paper, preceding text and implication hereinafter described.In certain embodiments, D is N-R
2In certain embodiments, E is CR
3In certain embodiments, R
3Be H.
Some embodiments of the invention are about compound, and wherein A is C
3Alkylidene group and B are C
1Alkylidene group, wherein A according to circumstances by 1 to 4 methyl substituted and B according to circumstances by 1 to 2 methyl substituted.In certain embodiments, A is-CHCH
2CH
2-and B be-CH
2-.Among some embodiment, The compounds of this invention can be represented by formula as follows (IIa):
Each parameter in its Chinese style (IIa) has this paper, preceding text and implication hereinafter described.
In certain embodiments, A is-CH
2-and B be-CH
2CH
2CH
2-.In certain embodiments, The compounds of this invention can be represented by formula as follows (IIb)
Each parameter in its Chinese style (IIb) has this paper, preceding text and implication hereinafter described.
In certain embodiments, A is-CH
2-, B is-CH
2CH
2CH
2-, and E is CH.
In certain embodiments, A is-CH
2-and B be-CH
2CH
2CH
2-, E is that CH and D are N-R
2
Some embodiments of the invention about wherein A and B all for according to circumstances by 1 to 4 methyl substituted C
2The compound of alkylidene group.In certain embodiments, A is-CH
2CH
2-or-CHCH
2-and B be-CH
2CH
2-.In certain embodiments, A and B are-CH
2CH
2-.In certain embodiments, The compounds of this invention can by formula as follows (IIc) and (IId) expression:
Its Chinese style (IIe) and (IId) in each parameter have this paper, preceding text and implication hereinafter described.In certain embodiments, A and B are-CH
2CH
2-and E be CH.In certain embodiments, A and B are-CH
2CH
2-, D is N-R
2And E is CR
3In certain embodiments, A and B are-CH
2CH
2-, and E is CH, and D is N-R
2Some embodiments of the invention can be expressed as formula as follows (IIf)
Each parameter in its Chinese style (IIf) has this paper, preceding text and implication hereinafter described.In certain embodiments, compound is formula (IIf) and R
3Be H.In other embodiments, K is a key.In other embodiments, K is-CH
2-or-CH
2CH
2-.
Some embodiments of the invention are about formula as follows (IIg) compound
Each parameter in its Chinese style (IIg) has this paper, preceding text and implication hereinafter described.In certain embodiments, R
3For H and Q are O (that is oxygen).
Some embodiments of the invention are about compound, and wherein A is C
2Alkylidene group and B are C
3Alkylidene group, wherein A and B are according to circumstances by 1 to 4 methyl substituted.In certain embodiments, A is-CH
2CH
2-or-CHCH
2-and B be-CH
2CH
2CH
2-; And can by formula as follows (IIh) and (IIi) expression:
Its Chinese style (IIh) and (III) in each parameter have this paper, preceding text and implication hereinafter described.
Some embodiments of the invention are about compound, and wherein A is C
3Alkylidene group and B are C
2Alkylidene group, wherein A and B are according to circumstances by 1 to 4 methyl substituted.In certain embodiments, A is-CHCH
2CH
2-and B be-CH
2CH
2-, said embodiment can be represented by formula as follows (IIk):
Each parameter in its Chinese style (IIk) has this paper, preceding text and implication hereinafter described.
Some embodiments of the invention are about wherein A and B are according to circumstances by I to 4 methyl substituted C
3The compound of alkylidene group.In certain embodiments, A is-CH
2CH
2CH
2-or-CHCH
2CH
2-and B be-CH
2CH
2CH
2-, and respectively by formula as follows (IIm) and (IIn) expression:
Its Chinese style (IIm) and (IIn) in each parameter have this paper, preceding text and implication hereinafter described.
Some embodiments of the invention are about wherein---be single bonded compound, said embodiment is represented by the formula that is described below (IIo):
Each parameter in its Chinese style (IIo) has this paper, preceding text and implication hereinafter described.
Some embodiments of the invention are the compound of N about E wherein.
Some embodiments of the invention are CR about E wherein
3Compound.
Some embodiments of the invention are about R wherein
3Compound for H.
In certain embodiments, E is that CH and D are N-R
2
In certain embodiments, B is that CH and D are CHR
2
Some embodiments of the invention are about wherein---be the compound of two keys.Should be appreciated that and work as
During for two key, then E is CR
3(being carbon atom) and E are not N (being nitrogen-atoms).
Some embodiments of the invention are about following compound, and wherein K looks the eyeball condition by 1 to 4 substituted C of substituting group that is selected from the group that is made up of following group
1-3Alkylidene group: C
1-3Alkyl, C
1-4Alkoxyl group, carboxyl, cyanic acid, C
1-3Alkylhalide group and halogen.In certain embodiments, K is-CH
2-Ji.In certain embodiments, K is-CH
2CH
2-Ji.
Some embodiments of the invention are the compound of key about K wherein; Said embodiment is represented by formula as follows (IIq):
Each parameter in its Chinese style (IIq) has this paper, preceding text and implication hereinafter described.In certain embodiments, Q is O (anticipating promptly Sauerstoffatom).
Some embodiments of the invention are about compound, and wherein D is CR
1R
2And can represent by formula as follows (IIt):
Each parameter in its Chinese style (IIt) has this paper, preceding text and implication hereinafter described.In certain embodiments, R
2Be selected from the group that forms by following group: H, amino, carboxamide groups, carboxyl, cyanic acid, C
3-6Naphthenic base, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, halogen and hydroxyl.In certain embodiments, R
2Be selected from the group that forms by following group: OCH
3, OCH
2CH
3, OCH
2CH
2CH
3, OCH (CH
3)
2, OCH
2(CH
2)
2CH
3, amino, carboxamide groups, carboxyl, cyanic acid, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, OCF
3, OCHF
2, CF
3, CHF
2And F.In certain embodiments, R
2For according to circumstances by 1 to 5 substituted C of substituting group that is selected from the group that forms by following group
1-8Alkyl, aryl or heteroaryl: C
1-5Acyl group, C
1-5Acyloxy, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkylamino, C
1-4Alkyl carboxamide groups, C
1-4Alkylthio carboxamide groups, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, C
1-4Alkylthio urea groups, C
1-4Alkyl urea groups, amino, carbonyl-C
1-6-alkoxyl group, carboxamide groups, carboxyl, cyanic acid, C
3-6-naphthenic base, C
3-6-naphthenic base-C
1-3-assorted alkylidene group, C
2-8Dialkyl amido, C
2-6Dialkyl group carboxamide groups, C
2-6Two alkylthio carboxamide groups, C
2-6Dialkyl group sulfoamido, C
1-4Alkylthio urea groups, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, C
1-4Alkylhalide group sulfinyl, C
1-4Alkylhalide group alkylsulfonyl, C
1-4Alkylhalide group, C
1-4Alkyl halide sulfenyl, halogen, heterocyclic radical, hydroxyl, hydroxyl amino and nitro.In a little embodiment, R
2Be selected from the group that forms by following group: CH
3, CH
2CH
3, CH
2CH
2CH
3, CH (CH
3)
2, CH (CH
3) (CH
2CH
3), CH
2(CH
2)
2CH
3, CH
2(CH
2)
3CH
3In certain embodiments, R
2Be selected from the CH of group that forms by following group
2OCH
3, CH
2CH
2OCH
3, CH
2OCH
2CH
3, CH
2OCH
2CH
2CH
3, CH
2CH
2OCH
2CH
3, CH
2CH
2OCH
2CH
2CH
3, CH
2OCH (CH
3)
2, CH
2OCH
2CH (CH
3)
2, CH
2CO
2H, CH
2CH
2CO
2H, CH
2OH, CH
2CH
2OH and CH
2CH
2CH
2OH.In certain embodiments, R
2Be selected from the group that forms by following group: CH
2SCH
3, CH
2SCH
2CH
3, CH
2SCH
2CH
2CH
3, CH
2SCH (CH
3)
2, CH
2SCH
2(CH
2)
2CH
3CH
2CH
2SCH
3, CH
2CH
2SCH
2CH
3, CH
2CH
2SCH
2CH
2CH
3, CH
2CH
2SCH (CH
3)
2, CH
2CH
2SCH
2(CH
2)
2CH
3, CH
2S (O) CH
3, CH
2S (O) CH
2CH
3, CH
2S (O) CH
2CH
2CH
3, CH
2S (O) CH (CH
3)
2, CH
2S (O) CH
2(CH
2)
2CH
3, CH
2CH
2S (O) CH
3, CH
2CH
2S (O) CH
2CH
3, CH
2CH
2S (O) CH
2CH
2CH
3, CH
2CH
2S (O) CH (CH
3)
2, CH
2H
2S (O) CH
2(CH
2)
2CH
3, CH
2S (O)
2CH
3, CH
2S (O)
2CH
2CH
3, CH
2S (O)
2CH
2CH
2CH
3, CH
2S (O)
2CH (CH
3)
2, CH
2S (O)
2CH
2(CH
2)
2CH
3, CH
2CH
2S (O)
2CH
3, CH
2CH
2S (O)
2CH
2CH
3, CH
2CH
2(O)
2CH
2CH
2CH
3, CH
2CH
2S (O)
2CH (CH
3)
2And CH
2CH
2S (O)
2CH
2(CH
2)
2CH
3In certain embodiments, R
2Be selected from the group that forms by following group: CH
2OCH
2-cyclopropyl, CH
2OCH
2-cyclobutyl, CH
2OCH
2-cyclopentyl, CH
2OCH
2-cyclohexyl, CH
2OCH
2CH
2-cyclopropyl, CH
2OCH
2CH
2-cyclobutyl, CH
2OCH
2CH
2-cyclopentyl, CH
2OCH
2CH
2-cyclohexyl, CH
2CH
2OCH
2-cyclopropyl, CH
2CH
2OCH
2-cyclobutyl, CH
2CH
2OCH
2-cyclopentyl, CH
2CH
2OCH
2-cyclohexyl, CH
2CH
2OCH
2CH
2-cyclopropyl, CH
2CH
2OCH
2CH
2-cyclobutyl, CH
2CH
2OCH
2CH
2-cyclopentyl and CH
2CH
2OCH
2CH
2-cyclohexyl.In certain embodiments, R
2Be selected from the group that forms by following group: 1,2,4-oxadiazole-3-base, 1,2,4-oxadiazole-5-base, 1,3; 4-oxadiazole-2-base, 1,2,4-triazole-5-base and 1,2,4-triazol-1-yl, 3-methyl isophthalic acid, 4-oxadiazole-5-base, 3-methyl isophthalic acid; 2,4-oxadiazole-5-base, 3-ethyl-1,2,4-oxadiazole-5-base, 3-ethyl-1,2,4-oxadiazole-5-base, 5-methyl isophthalic acid; 3,4-oxadiazole-2-base, 5-ethyl-1,3,4-oxadiazole-2-base, 3-methyl isophthalic acid, 2,4-triazole-5-base, 3-ethyl-1; 2,4-triazole-5-base, 3-methyl isophthalic acid, 2,4-triazol-1-yl, 3-ethyl-1,2; 4-triazol-1-yl, 5-methyl isophthalic acid, 2,4-triazol-1-yl and 5-ethyl-1,2,4-triazol-1-yl.
R in certain embodiments
2For the heteroaryl that comprises 5 atoms in the aromatic ring and be expressed from the next:
Table 2A
Wherein 5-unit heteroaryl is at any position keyed jointing that gets of ring, and for example the imidazoles basic ring can be located keyed jointing one of one of theheterocyclic nitrogen atom (being imidazoles-1-yl) or ring carbon atom (being imidazoles-2-base, imidazol-4 yl or imidazoles-5-yl).In certain embodiments, R
2For according to circumstances by 1 to 4 the substituted 5-of the substituting group that is selected from the group that forms by following group unit heteroaryl (such as but not limited to listed among the table 2A) C
1-5Acyl group, C
1-5Acyloxy, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkylamino, C
1-4Alkyl carboxamide groups, C
1-4Alkylthio carboxamide groups, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, C
1-4Alkylthio urea groups, C
1-4Alkyl urea groups, amino, carbonyl-C
1-6-alkoxyl group, carboxamide groups, carboxyl, cyanic acid, C
3-6-naphthenic base, C
3-6-naphthenic base-C
1-3-assorted alkylidene group, C
2-8Dialkyl amido, C
2-6Dialkyl group carboxamide groups, C
2-6Two alkylthio carboxamide groups, C
2-6Dialkyl group sulfoamido, C
1-4Alkylthio urea groups, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, C
1-4Alkylhalide group sulfinyl, C
1-4Alkylhalide group alkylsulfonyl, C
1-4Alkylhalide group, C
1-4Alkyl halide sulfenyl, halogen, heterocyclic radical, hydroxyl, hydroxyl amino and nitro.
R in certain embodiments
2For the heteroaryl that comprises 5 atoms in the aromatic ring and be expressed from the next:
Wherein 5-unit heteroaryl is as indicated above at any position keyed jointing that gets.In certain embodiments, R
2For according to circumstances by 1 to 4 substituted 5-heteroaryl: C of unit of the substituting group that is selected from the group that forms by following group
1-5Acyl group, C
1-5Acyloxy, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkylamino, C
1-4Alkyl carboxamide groups, C
1-4Alkylthio carboxamide groups, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, C
1-4Alkylthio urea groups, C
1-4Alkyl urea groups, amino, carbonyl-C
1-6-alkoxyl group, carboxamide groups, carboxyl, cyanic acid, C
3-6-naphthenic base-C
1-3-assorted alkylidene group, C
2-8Dialkyl amido, C
2-6Dialkyl group carboxamide groups, C
2-6Two alkylthio carboxamide groups, C
2-6Dialkyl group sulfoamido, C
1-4Alkylthio urea groups, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, C
1-4Alkylhalide group sulfinyl, C
1-4Alkylhalide group alkylsulfonyl, C
1-4Alkylhalide group, C
1-4Alkyl halide sulfenyl, halogen, heterocyclic radical, hydroxyl, hydroxyl amino and nitro.
In certain embodiments, R
2Serve as reasons and for example show the heterocyclic radical of chemical formulation among the 2B.
Table 2B
Should be appreciated that except as otherwise noted, otherwise one of heterocyclic radical shown in the table 2B to 2E can such as chemical formula separately permission at any ring carbon or theheterocyclic nitrogen atom place keyed jointing.For example, 2,5-diketo-imidazolidyl can be located to connect and produce following chemical formula respectively at one of ring carbon or two theheterocyclic nitrogen atoms:
In certain embodiments, R
2Serve as reasons and for example show the heterocyclic radical of chemical formulation among the 2C.
Table 2C
In certain embodiments, R
2Serve as reasons and for example show the heterocyclic radical of chemical formulation among the 2D.
Table 2D
In certain embodiments, R
2Serve as reasons and for example show the heterocyclic radical of chemical formulation among the 2E.
Table 2E
In certain embodiments, R
2Serve as reasons and for example show the heterocyclic radical of chemical formulation among the 2F, wherein the C on each theheterocyclic nitrogen atom
1-6Alkyl can be identical or different.
Table 2F
In certain embodiments, R
2Serve as reasons and for example show the heterocyclic radical of chemical formulation among the 2G, wherein the C on each theheterocyclic nitrogen atom
1-6Alkyl can be identical or different.
Table 2G
Some embodiments of the invention are about formula (IIt) compound, and R
2For-Ar
2-Ar
3, Ar wherein
2And Ar
3Independent of according to circumstances by 1 to 5 substituted aryl of substituting group that is selected from the group that forms by following group or heteroaryl: H, C
1-5Acyl group, C
1-5Acyloxy, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkyl carboxamide groups, C
1-4Alkylthio carboxamide groups, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, amino, carbonyl-C
1-6-alkoxyl group, carboxamide groups, carboxyl, cyanic acid, C
3-6-naphthenic base, C
2-6Dialkyl group carboxamide groups, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, halogen, hydroxyl and nitro.
Ar in certain embodiments
2For the heteroaryl that comprises 5 atoms in the aromatic ring and by the chemical formulation in the following table 3:
Table 3
Wherein 5-unit heteroaryl is in any position keyed jointing that gets of ring, and for example the imidazoles basic ring can be located to connect and Ar in one of one of theheterocyclic nitrogen atom (being imidazoles-1-yl) or ring carbon atom (being imidazoles-2-base, imidazol-4 yl or imidazoles-5-yl)
3Can be bonded to any remaining annular atoms that gets.In certain embodiments, Ar
2Be heteroaryl and Ar
3Be phenyl.In certain embodiments, Ar
2Be phenyl and Ar
3Be heteroaryl (for example being selected from the heteroaryl among the preceding text table 2A).In certain embodiments, heteroaryl and phenyl are replaced by 1 to 5 substituting group that is selected from the group that is made up of following group according to circumstances: H, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkyl carboxamide groups, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, halogen, hydroxyl and nitro.
Some embodiments of the invention are about R wherein
2Formula (IIt) compound for formula (B):
Wherein:
R
19Be C
1-8Alkyl or C
3-7Naphthenic base; And R
20Be F, C1, Br or CN.
Some embodiments of the invention are about R wherein
2Formula (IIt) compound for formula (C):
Wherein:
G is selected from the C of group (O), C (O) NR that is made up of following group
25, C (O) O, OC (O), C (S), C (S) NR
25, C (S) O, OC (S), CR
25R
26, O, S, S (O) and S (O)
2, R wherein
25And R
26Independent is H or C
1-8Alkyl; And
R
24For according to circumstances by 1 to 5 substituted C of substituting group that is selected from the group that forms by following group
1-8Alkyl, C
3-7Naphthenic base, phenyl or heteroaryl: C
1-5Acyl group, C
1-5Acyloxy, C
1-4Alkoxyl group, C
1-7Alkyl, C
1-4Alkylamino, C
1-4Alkyl carboxamide groups, C
1-4Alkylthio carboxamide groups, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, C
1-4Alkylthio urea groups, C
1-4Alkyl urea groups, amino, carbonyl-C
1-6-alkoxyl group, carboxamide groups, carboxyl, cyanic acid, C
3-7-naphthenic base, C
2-8Dialkyl amido, C
2-6Dialkyl group carboxamide groups, C
2-6Two alkylthio carboxamide groups, C
2-6Dialkyl group sulfoamido, C
1-4Alkylthio urea groups, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, C
1-4Alkylhalide group sulfinyl, C
1-4Alkylhalide group alkylsulfonyl, C
1-4Alkylhalide group, C
1-4Alkyl halide sulfenyl, halogen, hydroxyl, hydroxyl amino and nitro.
Some embodiments of the invention are about formula (IIt) compound, wherein R
2For formula (C) and G are selected from by C (O), C (O) NR
25, C (O) O, OC (O), C (S), C (S) NR
25, C (S) O, OC (S) or CR
25R
26The group that is formed.In certain embodiments, R
24For according to circumstances by 1 to 5 substituted C of substituting group that is selected from the group that forms by following group
1-8Alkyl: C
1-5Acyl group, C
1-4Alkoxyl group, C
1-7Alkyl, C
1-4Alkyl carboxamide groups, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, carboxamide groups, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, C
1-4Alkylhalide group sulfinyl, C
1-4Alkylhalide group alkylsulfonyl, C
1-4Alkylhalide group, halogen and hydroxyl.
Some embodiments of the invention are about formula (IIt) compound, wherein R
2For formula (C) and G are selected from by C (O), C (O) NR
25, C (O) O, OC (O), C (S), C (S) NR
25, C (S) O, OC (S) or CR
25R
26The group that is formed.In certain embodiments, R
24For according to circumstances by 1 to 5 substituted phenyl C of substituting group that is selected from the group that forms by following group
1-5Acyl group, C
1-4Alkoxyl group, C
1-7Alkyl, C
1-4Alkyl carboxamide groups, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, carboxamide groups, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, C
1-4Alkylhalide group sulfinyl, C
1-4Alkylhalide group alkylsulfonyl, C
1-4Alkylhalide group, halogen and hydroxyl.
Some embodiments of the invention are about formula (IIt) compound, wherein R
2For formula (C) and G are selected from by C (O), C (O) NR
25, C (O) O, OC (O), C (S), C (S) NR
25, C (S) O, OC (S) and CR
25R
26The group that is formed.In certain embodiments, R
24For according to circumstances by 1 to 5 the substituted heteroaryl of substituting group that is selected from the group that forms by following group: C
1-5Acyl group, C
1-4Alkoxyl group, C
1-7Alkyl, C
1-4Alkyl carboxamide groups, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, carboxamide groups, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, C
1-4Alkylhalide group sulfinyl, C
1-4Alkylhalide group alkylsulfonyl, C
1-4Alkylhalide group, halogen and hydroxyl.In certain embodiments, R
24Be selected from the group that forms by pyridyl, pyridazinyl, pyrimidyl and pyrazinyl.In certain embodiments, R
24Be pyridyl.
Some embodiments of the invention are about R wherein
25And R
26Independent is H or C
1-2The compound of alkyl.
Some embodiments of the invention are about formula (IIt) compound, wherein R
2For formula (C) and G are selected from by O, S, S (O) or S (O)
2The group that is formed.In certain embodiments, R
24For according to circumstances by 1 to 5 substituted C of substituting group that is selected from the group that forms by following group
1-8Alkyl: C
1-5Acyl group, C
1-4Alkoxyl group, C
1-7Alkyl, C
1-4Alkyl carboxamide groups, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, carboxamide groups, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, C
1-4Alkylhalide group sulfinyl, C
1-4Alkylhalide group alkylsulfonyl, C
1-4Alkylhalide group, halogen and hydroxyl.
Some embodiments of the invention are about formula (IIt) compound, wherein R
2For formula (C) and G are selected from by O, S, S (O) or S (O)
2The group that is formed.In certain embodiments, R
24For according to circumstances by 1 to 5 substituted phenyl C of substituting group that is selected from the group that forms by following group
1-5Acyl group, C
1-4Alkoxyl group, C
1-7Alkyl, C
1-4Alkyl carboxamide groups, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, carboxamide groups, C
1-4Fontanel alkoxyl group, C
1-4Alkylhalide group, C
1-4Alkylhalide group sulfinyl, C
1-4Alkylhalide group alkylsulfonyl, C
1-4Alkylhalide group, halogen and hydroxyl.
Some embodiments of the invention are about formula (IIt) compound, wherein R
2For formula (C) and G are selected from by O, S, S (O) or S (O)
2The group that is formed.In certain embodiments, R
24For according to circumstances by 1 to 5 the substituted heteroaryl of substituting group that is selected from the group that forms by following group: C
1-5Acyl group, C
1-4Alkoxyl group, C
1-7Alkyl, C
1-4Alkyl carboxamide groups, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, carboxamide groups, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, C
1-4Alkylhalide group sulfinyl, C
1-4Alkylhalide group alkylsulfonyl, C
1-4Alkylhalide group, halogen and hydroxyl.In certain embodiments, R
24Be selected from the group that forms by pyridyl, pyridazinyl, pyrimidyl and pyrazinyl.In certain embodiments, R
24Be pyridyl.
Some embodiments of the invention are about R wherein
1Compound for H.
Some embodiments of the invention are about R wherein
2Compound for formula (C) group:
Wherein G is:
-NHC (O)-,-NH-,-NHC (O) O-,-CH
2NHC (O)-or key; And R
24For H, be selected from by C by 1 to 2 according to circumstances separately
1-4Alkoxyl group and C
1-7The substituted C of the substituting group of the group that alkyl is formed
1-8Alkyl or heteroaryl.
In certain embodiments, R
2Be selected from the group that forms by following group:
Some embodiments of the invention are about R wherein
2Compound for formula (C):
Wherein
G is-CR
25R
26C (O)-,-C (O)-,-C (O) NR
25-,-C (O) O-,-C (S) NR
25-,-CR
25R
26-, or key, wherein R
25And R
26Independent separately is H or C
1-8Alkyl; And R
24For H, separately according to circumstances by 1 to 5 substituted C of substituting group that is selected from the group that forms by following group
1-8Alkyl, C
3-7Naphthenic base, phenyl, heteroaryl or heterocyclic radical: C
1-4Alkoxyl group, C
1-7Alkyl, C
1-4Alkylamino, amino, carbonyl-C
1-6-alkoxyl group, carboxyl, C
3-7Naphthenic base, C
2-8Dialkyl amido, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, halogen, heteroaryl, heterocyclic radical, hydroxyl and nitro, wherein said C
1-4Alkoxyl group, C
1-7Alkyl, C
1-4Alkylamino, heteroaryl and phenyl are replaced by 1 to 5 substituting group that is selected from the group that is made up of following group separately according to circumstances: C
1-4Alkoxyl group, carbonyl-C
1-6-alkoxyl group, carboxamide groups, carboxyl, C
3-7Naphthenic base, halogen, heterocyclic radical and phenyl.
In certain embodiments, formula (C) is-CR
25R
26C (O) R
24
In certain embodiments, formula (C) is-C (O) R
24
In certain embodiments, formula (C) is-C (O) NR
25R
24
In certain embodiments, formula (C) is-R
24(promptly-G-is a key).
In certain embodiments, formula (C) is-C (O) OR
24
In certain embodiments, formula (C) is-C (S) NR
25R
24
In certain embodiments, formula (C) is-CR
25R
26R
24
Some embodiments of the invention are about compound, wherein R
2For-C (O) OR
24And R
24For separately according to circumstances by 1 to 5 substituted C of substituting group that is selected from the group that forms by following group
1-8Alkyl, C
3-7Naphthenic base, phenyl, heteroaryl or heterocyclic radical: C
1-4Alkoxyl group, C
1-7Alkyl, C
1-4Alkyl sulphonyl, amino, carbonyl-C
1-6-alkoxyl group, carboxyl, cyanic acid, C
3-7Naphthenic base, C
2-8Dialkyl amino, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, halogen, heteroaryl, heterocyclic radical, hydroxyl, phenyl, phenoxy and sulfonic acid, wherein said C
1-7Alkyl, phenyl and phenoxy are selected from by amino, C by 1 to 5 separately according to circumstances
1-4The substituting group of the group that halogen alkoxyl group and heterocyclic radical are formed replaces.
Some embodiments of the invention are about compound, wherein R
2For-C (O) OR
24And R
24For separately according to circumstances by 1 to 5 substituted C of substituting group that is selected from the group that forms by following group
1-8Alkyl or C
3-7Naphthenic base: C
1-4Alkoxyl group, C
1-7Alkyl, C
1-4Alkyl sulphonyl, carboxyl, cyanic acid, C
3-7Naphthenic base, C
2-8Dialkyl amido, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, halogen, heteroaryl, heterocyclic radical, hydroxyl, phenyl, phenoxy and sulfonic acid.
Some embodiments of the invention are about compound, wherein R
2For-C (O) OR
24And R
24Be C
1-8Alkyl or C
3-7Naphthenic base, wherein said C
3-7Naphthenic base is selected from by C by 1 to 5 according to circumstances
1-4Alkoxyl group, C
1-7Alkyl, carboxyl, C
2-8The substituting group of the group that dialkyl amido and halogen are formed replaces.
Some embodiments of the invention are about compound, wherein R
2For-C (O) OR
24And R
24Be C
1-8Alkyl or C
3-7Naphthenic base.
Some embodiments of the invention are about compound, wherein R
2For-C (O) R
24And R
24For separately according to circumstances by 1 to 5 substituted C of substituting group that is selected from the group that forms by following group
1-8Alkyl, C
3-7Naphthenic base, phenyl, heteroaryl or heterocyclic radical C
2-6Thiazolinyl, C
1-4Alkoxyl group, C
1-7Alkyl, C
1-4Alkyl sulphonyl, amino, carbonyl-C
1-6-alkoxyl group, carboxyl, cyanic acid, C
3-7Naphthenic base, C
2-8Dialkyl amido, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, halogen, heteroaryl, heterocyclic radical, hydroxyl, phenyl, phenoxy and sulfonic acid, wherein said C
1-7Alkyl, phenyl and phenoxy are selected from by amino, C by 1 to 5 separately according to circumstances
1-4The substituting group of the group that halogen alkoxyl group and heterocyclic radical are formed replaces.
Some embodiments of the invention are about compound, wherein R
2For-C (O) R
24And R
24For separately according to circumstances by 1 to 5 substituted C of substituting group that is selected from the group that forms by following group
1-8Alkyl, heteroaryl or heterocyclic radical: H, C
1-4Alkoxyl group, C
1-7Alkyl, amino, carboxyl, halogen, heteroaryl, hydroxyl, phenoxy and sulfonic acid, wherein said C
1-7Alkyl and phenoxy are selected from by amino, C by 1 to 5 according to circumstances
1-4The substituting group of the group that halogen alkoxyl group and heterocyclic radical are formed replaces.
Some embodiments of the invention are about compound, wherein R
2For-C (O) R
24Or R
24, and R
24For separately according to circumstances by 1 to 5 substituted C of substituting group that is selected from the group that forms by following group
1-8Alkyl, C
3-7Naphthenic base, phenyl, heteroaryl or heterocyclic radical: C
1-5Acyl group, C
2-6Thiazolinyl, C
1-4Alkoxyl group, C
1-7Alkyl, C
1-4Alkyl sulphonyl, amino, carbonyl-C
1-6Alkoxyl group, carboxyl, cyanic acid, C
3-7Naphthenic base, C
2-8Dialkyl amido, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, halogen, heteroaryl, heterocyclic radical, hydroxyl, phenyl, phenoxy and sulfonic acid, wherein said C
1-7Alkyl, phenyl and phenoxy are selected from by amino, C by 1 to 5 separately according to circumstances
1-4The substituting group of the group that halogen alkoxyl group and heterocyclic radical are formed replaces.
Some embodiments of the invention are about compound, wherein R
2For-CH
2R
24Or-R
24, and R
24For separately according to circumstances by 1 to 5 substituted C of substituting group that is selected from the group that forms by following group
1-8Alkyl, C
3-7Naphthenic base or heteroaryl, C
1-5Acyl group, C
2-6Thiazolinyl, C
1-4Alkoxyl group, carbonyl-C
1-6-alkoxyl group, carboxyl, cyanic acid, C
3-7Naphthenic base and hydroxyl.
Some embodiments of the invention are about compound, wherein R
2For-S (O)
2R
24And R
24For separately according to circumstances by 1 to 5 substituted C of substituting group that is selected from the group that forms by following group
1-8Alkyl, C
3-7Naphthenic base, phenyl, heteroaryl or heterocyclic radical: C
2-6Thiazolinyl, C
1-4Alkoxyl group, C
1-7Alkyl, C
1-4Alkyl sulphonyl, amino, carbonyl-C
1-6-alkoxyl group, carboxyl, cyanic acid, C
3-7Naphthenic base, C
2-8Dialkyl amido, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, halogen, heteroaryl, heterocyclic radical, hydroxyl, phenyl, phenoxy and sulfonic acid, wherein said C
1-7Alkyl, phenyl and phenoxy are selected from by amino, C by 1 to 5 separately according to circumstances
1-4The substituting group of the group that halogen alkoxyl group and heterocyclic radical are formed replaces.
Some embodiments of the invention wherein are-S (O) about compound
2R
24And R
24Be C
1-8Alkyl or heteroaryl, and said heteroaryl is according to circumstances by 1 to 5 C
1-7Alkyl replaces.
Some embodiments of the invention are about compound, wherein R
2For-CH
2(O) R
24And R
24For separately according to circumstances by 1 to 5 substituted C of substituting group that is selected from the group that forms by following group
1-8Alkyl, C
3-7Naphthenic base, phenyl, heteroaryl or heterocyclic radical: C
2-6Thiazolinyl, C
1-4Alkoxyl group, C
1-7Alkyl, C
1-4Alkyl sulphonyl, amino, carbonyl-C
1-6-alkoxyl group, carboxyl, cyanic acid, C
3-7Naphthenic base, C
2-8Dialkyl amido, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, halogen, heteroaryl, heterocyclic radical, hydroxyl, phenyl, phenoxy and sulfonic acid, wherein said C
1-7Alkyl, phenyl and phenoxy are selected from by amino, C by 1 to 5 separately according to circumstances
1-4The substituting group of the group that halogen alkoxyl group and heterocyclic radical are formed replaces.
Some embodiments of the invention are about compound, wherein R
2For-CH
2C (O) R
24And R
24For separately according to circumstances by 1 to 5 the substituted phenyl of substituting group, heteroaryl or heterocyclic radical: C that is selected from the group that forms by following group
1-4Alkoxyl group, C
1-7Alkyl, C
1-4Alkyl sulphonyl, cyanic acid, C
2-8Dialkyl amido, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, halogen, heteroaryl and phenyl.
Some embodiments of the invention are about compound, wherein R
2For-CH
2C (O) NHR
24And R
24For separately according to circumstances by 1 to 5 substituted C of substituting group that is selected from the group that forms by following group
1-8Alkyl, C
3-7Naphthenic base, phenyl, heteroaryl or heterocyclic radical: C
2-6Thiazolinyl, C
1-4Alkoxyl group, C
1-7Alkyl, C
1-4Alkyl sulphonyl, amino, carbonyl-C
1-6-alkoxyl group, carboxyl, cyanic acid, C
3-7Naphthenic base, C
2-8Dialkyl amido, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, halogen, heteroaryl, heterocyclic radical, hydroxyl, phenyl, phenoxy and sulfonic acid, wherein said C
1-7Alkyl, phenyl and phenoxy are selected from by amino, C by 1 to 5 separately according to circumstances
1-4The substituting group of the group that halogen alkoxyl group and heterocyclic radical are formed replaces.
Some embodiments of the invention are about compound, wherein R
2For-CH
2C (O) NHR
24And R wherein
24For according to circumstances by 1 to 5 the substituted phenyl of substituting group that is selected from the group that forms by following group: C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkylhalide group and halogen.
Some embodiments of the invention are N-R about D wherein
2Compound, and it is represented by formula (IIv):
Each parameter in its Chinese style (IIv) has this paper, preceding text and implication hereinafter described.In certain embodiments, R
2For according to circumstances by 1 to 5 substituted C of substituting group that is selected from the group that forms by following group
1-8Alkyl, aryl or heteroaryl: C
1-5Acyl group, C
1-5Acyloxy, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkylamino, C
1-4Alkyl carboxamide groups, C
1-4Alkylthio carboxamide groups, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, C
1-4Alkylthio urea groups, C
1-4Alkyl urea groups, amino, carbonyl-C
1-6-alkoxyl group, carboxamide groups, carboxyl, cyanic acid, C
3-6-naphthenic base, C
3-6-naphthenic base-C
1-3-assorted alkylidene group, C
2-8Dialkyl amido, C
2-6Dialkyl group carboxamide groups, C
2-6Two alkylthio carboxamide groups, C
2-6Dialkyl group sulfoamido, C
1-4Alkylthio urea groups, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, C
1-4Alkylhalide group sulfinyl, C
1-4Alkylhalide group alkylsulfonyl, C
1-4Alkylhalide group, C
1-4Alkyl halide sulfenyl, halogen, heterocyclic radical, hydroxyl, hydroxyl amino and nitro.In certain embodiments, R
2Be pyridyl.In certain embodiments, R
2Be the 2-pyridyl.
In certain embodiments, R
2Be selected from by CH
2CH
2C (CH
3)
3, CH
2CH
2CH (CH
3)
2And CH
2(CH
2)
4CH
3The group that is formed.In certain embodiments, R
2Be selected from the group that forms by following group: CH
3, CH
2CH
3, CH
2CH
2CH
3, CH (CH
3)
2, CH (CH
3) (CH
2CH
3), CH
2(CH
2)
2CH
3And CH
2(CH
3)
3CH
3In certain embodiments, R
2Be selected from the group that forms by following group: CH
2OCH
3, CH
2CH
2OCH
3, CH
2OCH
2CH
3, CH
2OCH
2CH
2CH
3, CH
2CH
2OCH
2CH
3, CH
2CH
2OCH
2CH
2CH
3, CH
2OCH (CH
3)
2, CH
2OCH
2CH (CH
3)
2, CH
2CO
2H, CH
2CH
2CO
2H, CH
2OH, CH
2CH
2OH and CH
2CH
2CH
2OH.In certain embodiments, R
2Be selected from the group that forms by following group: CH
2SCH
3, CH
2SCH
2CH
3, CH
2SCH
2CH
2CH
3, CH
2SCH (CH
3)
2, CH
2SCH
2(CH
2)
2CH
3, CH
2CH
2SCH
3, CH
2CH
2SCH
2CH
3, CH
2CH
2SCH
2CH
2CH
3, CH
2CH
2SCH (CH
3)
2, CH
2CH
2SCH
2(CH
2)
2CH
3, CH
2S (O) CH
3, CH
2S (O) CH
2CH
3, CH
2S (O) CH
2CH
2CH
3, CH
2S (O) CH (CH
3)
2, CH
2S (O) CH
2(CH
2)
2CH
3, CH
2CH
2S (O) CH
3, CH
2CH
2S (O) CH
2CH
3, CH
2CH
2S (O) CH
2CH
2CH
3, CH
2CH
2S (O) CH (CH
3)
2, CH
2CH
2S (O) CH
2(CH
2)
2CH
3, CH
2S (O)
2CH
3, CH
2S (O)
2CH
2CH
3, CH
2S (O)
2CH
2CH
2CH
3, CH
2S (O)
2CH (CH
3)
2, CH
2S (O)
2CH
2(CH
2)
2CH
3, CH
2CH
2S (O)
2CH
3, CH
2CH
2S (O)
2CH
2CH
3, CH
2CH
2S (O)
2CH
2CH
2CH
3, CH
2CH
2S (O)
2CH (CH
3)
2And CH
2CH
2S (O)
2CH
2(CH
2)
2CH
3In certain embodiments, R
2Be CH
2-cyclopropyl.In certain embodiments, R
2Be selected from the group that forms by following group: CH
2OCH
2-cyclopropyl, CH
2OCH
2-cyclobutyl, CH
2OCH
2-cyclopentyl, CH
2OCH
2-cyclohexyl, CH
2OCH
2CH
2-cyclopropyl, CH
2OCH
2CH
2-cyclobutyl, CH
2OCH
2CH
2-cyclopentyl, CH
2OCH
2CH
2-cyclohexyl, CH
2CH
2OCH
2-cyclopropyl, CH
2CH
2OCH
2-cyclobutyl, CH
2CH
2OCH
2-cyclopentyl, CH
2CH
2OCH
2-cyclohexyl, CH
2CH
2OCH
2CH
2-cyclopropyl, CH
2CH
2OCH
2CH
2-cyclobutyl, CH
2CH
2OCH
2CH
2-cyclopentyl and CH
2CH
2OCH
2CH
2-cyclohexyl.In certain embodiments, R
2Be selected from the group 1,2 that forms by following group, 4-oxadiazole-3-base 1,2,4-oxadiazole-5-base, 1,3; 4-oxadiazole-2-base, 1,2,4-triazole-5-base and 1,2,4-triazol-1-yl, 3-methyl isophthalic acid, 2; 4-oxadiazole-5-base, 3-methyl isophthalic acid, 2,4-oxadiazole-5-base, 3-ethyl-1,2,4-oxadiazole-5-base, 3-ethyl-1,2; 4-oxadiazole-5-base, 5-methyl isophthalic acid, 3,4-oxadiazole-2-base, 5-ethyl-1,3,4-oxadiazole-2-base, 3-methyl isophthalic acid, 2; 4-triazole-5-base, 3-ethyl-1,2,4-triazole-5-base, 3-methyl isophthalic acid, 2,4-triazol-1-yl, 3-ethyl-1,2; 4-triazol-1-yl, 5-methyl isophthalic acid, 2,4-triazol-1-yl and 5-ethyl-1,2,4-triazol-1-yl.
In certain embodiments, compound is formula (IIv) and R
2For in ring, comprising the heteroaryl of 5 atoms, and be selected from group shown in the table 2A.In certain embodiments, R
2For according to circumstances by 1 to 4 the substituted 5-of the substituting group that is selected from the group that forms by following group unit heteroaryl; C
1-5Acyl group, C
1-5Acyloxy, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkylamino, C
1-4Alkyl carboxamide groups, C
1-4Alkylthio carboxamide groups, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, C
1-4Alkylthio urea groups, C
1-4Alkyl urea groups, amino, carbonyl-C
1-6-alkoxyl group, carboxamide groups, carboxyl, cyanic acid, C
3-6-naphthenic base-C
1-3-assorted alkylidene group, C
2-8Dialkyl amido, C
2-6Dialkyl group carboxamide groups, C
2-6Two alkylthio carboxamide groups, C
2-6Dialkyl group sulfoamido, C
1-4Alkylthio urea groups, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, C
1-4Alkylhalide group sulfinyl, C
1-4Alkylhalide group alkylsulfonyl, C
1-4Alkylhalide group, C
1-4Alkyl halide sulfenyl, halogen, heterocyclic radical, hydroxyl, hydroxyl amino and nitro.
In certain embodiments, R
2For being selected from like table 2B to the heterocyclic radical of showing group shown in the 2G.
Some embodiments of the invention are about formula (IIv) compound, and R
2For-Ar
2-Ar
3, Ar wherein
2And Ar
3Independent of according to circumstances by 1 to 5 substituted aryl of substituting group that is selected from the group that forms by following group or heteroaryl: H, C
1-5Acyl group, C
1-5Acyloxy, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkyl carboxamide groups, C
1-4Alkylthio carboxamide groups, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, amino, carbonyl-C
1-6-alkoxyl group, carboxamide groups, carboxyl, cyanic acid, C
3-6-naphthenic base, C
2-6Dialkyl group carboxamide groups, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, halogen, hydroxyl and nitro.In certain embodiments, Ar
2For the heteroaryl that on aromatic nucleus, comprises 5 atoms and be selected from group shown in the table 3.In certain embodiments, Ar
2Be heteroaryl and Ar
3Be phenyl.In certain embodiments, Ar
2Be phenyl and Ar
3Be heteroaryl (for example being selected from the heteroaryl of preceding text table 2A or table 4).In certain embodiments, heteroaryl and said phenyl are replaced by 1 to 5 substituting group that is selected from the group that is made up of following group according to circumstances: C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkyl carboxamide groups, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, cyanic acid, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, halogen, hydroxyl and nitro.
Some embodiments of the invention are N-R about D wherein
2Compound.In certain embodiments, R
2Be formula (B):
R wherein
19Be C
1-8Alkyl or C
3-7Naphthenic base; And R
20Be F, Cl, Br or CN.
Some embodiments of the invention are about R wherein
2Formula (IIv) compound for formula (C):
Wherein G is selected from the group that is made up of following group: C (O), C (O) NR
25, C (O) O, C (S), C (S) NR
25, C (S) O, CR
25R
26And S (O)
2, R wherein
25And R
26Independent is H or C
1-8Alkyl, and
R
24For according to circumstances by 1 to 5 substituted C of substituting group that is selected from the group that forms by following group
1-8Alkyl, C
3-7Naphthenic base, phenyl or heteroaryl: C
1-5Acyl group, C
1-5Acyloxy, C
1-4Alkoxyl group, C
1-7Alkyl, C
1-4Alkylamino, C
1-4Alkyl carboxamide groups, C
1-4Alkylthio carboxamide groups, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, C
1-4Alkylthio urea groups, C
1-4Alkyl urea groups, amino, carbonyl-C
1-6-alkoxyl group, carboxamide groups, carboxyl, cyanic acid, C
3-7-naphthenic base, C
2-8Dialkyl amido, C
2-6Dialkyl group carboxamide groups, C
2-6Two alkylthio carboxamide groups, C
2-6Dialkyl group sulfoamido, C
1-4Alkylthio urea groups, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, C
1-4Alkylhalide group sulfinyl, C
1-4Alkylhalide group alkylsulfonyl, C
1-4Alkylhalide group, C
1-4Alkyl halide sulfenyl, halogen, hydroxyl, hydroxyl amino and nitro.
Some embodiments of the invention are about formula (IIv) compound, wherein R
2Be formula (C) and R
24For according to circumstances by 1 to 5 substituted C of substituting group that is selected from the group that forms by following group
1-8Alkyl: C
1-5Acyl group, C
1-4Alkoxyl group, C
1-7Alkyl, C
1-4Alkyl carboxamide groups, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, carboxamide groups, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, C
1-4Alkylhalide group sulfinyl, C
1-4Alkylhalide group alkylsulfonyl, C
1-4Alkylhalide group, halogen and hydroxyl.
In certain embodiments, group-G-R
24Be selected from the group that forms by following group: C (O) CH
3, C (O) CH
2CH
3, C (O) CH
2CH
2CH
3, C (O) CH (CH
3)
2, C (O) CH
2CH
2CH
2CH
3, C (O) C (CH
3)
3, C (O) CH
2C (CH
3)
3, CH
3, CH
2CH
3, CH
2CH
2CH
3, CH (CH
3)
2, CH (CH
3) (CH
2CH
3), CH
2(CH
2)
2CH
3, C (CH
3)
3, CH
2(CH
2)
3CH
3, C (O) NHCH
3, C (O) NHCH
2CH
3, C (O) NHCH
2CH
2CH
3, C (O) NHCH (CH
3)
2, C (O) NHCH
2(CH
2)
2CH
3, C (O) N (CH
3)
2, C (O) N (CH
3) CH
2CH
3, C (O) NH (CH
2CH
3)
2, CO
2CH
3, CO
2CH
2CH
3, CO
2CH
2CH
2CH
3, CO
2CH (CH
3)
2, CO
2CH
2(CH
2)
2CH
3, CO
2C (CH
3)
3, CO
2CH (CH
3) CH
2CH
3, CO
2CH
2CH (CH
3)
2, CO
2CH
2(CH
2)
3CH
3, CO
2CH (CH
3) CH
2CH
2CH
3, CO
2CH
2CH (CH
3) CH
2CH
3, CO
2CH
2CH
2CH (CH
3)
2And CO
2CH
2C (CH
3)
3
Some embodiments of the invention are about formula (IIv) compound, wherein R
2Be formula (C) and R
24For according to circumstances by 1 to 5 the substituted phenyl of substituting group that is selected from the group that forms by following group: C
1-5Acyl group, C
1-4Alkoxyl group, C
1-7Alkyl, C
1-4Alkyl carboxamide groups, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, carboxamide groups, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, C
1-4Alkylhalide group sulfinyl, C
1-4Alkylhalide group alkylsulfonyl, C
1-4Alkylhalide group, halogen and hydroxyl.
Some embodiments of the invention are about formula (IIv) compound, wherein R
2Be formula (C) and R
24For according to circumstances by 1 to 5 substituted heteroaryl C of substituting group that is selected from the group that forms by following group
1-5Acyl group, C
1-4Alkoxyl group, C
1-7Alkyl, C
1-4Alkyl carboxamide groups, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, carboxamide groups, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, C
1-4Alkylhalide group sulfinyl, C
1-4Alkylhalide group alkylsulfonyl, C
1-4Alkylhalide group, halogen and hydroxyl.In certain embodiments, R
24Be selected from the group that forms by pyridyl, pyridazinyl, pyrimidyl and pyrazinyl.In certain embodiments, R
24Be pyridyl.
Some embodiments of the invention are about R wherein
25And R
26Independent is H or C
1-2Alkylate.
In certain embodiments, A and B are-CH
2CH
2-, D is NR
2, E be CH,
For singly-bound and K are singly-bound, said embodiment can be represented by formula as follows (IIx):
Each parameter in its Chinese style (IIx) has this paper, preceding text and implication hereinafter described.In certain embodiments, compound is that formula (IIx) and Q are O (being Sauerstoffatom) or NH.
In certain embodiments, The compounds of this invention is wherein R of formula (IIx)
2Be formula (C); Said embodiment can be represented by formula as follows (IIy):
Each parameter in its Chinese style (IIy) has this paper, preceding text and implication hereinafter described.In certain embodiments, G is C (O), C (O) NR
25, C (O) O, C (S), C (S) NR
25, C (S) O, CR
25R
26Or S (O)
2In certain embodiments, G is C (O) and can be represented by formula as follows (IIz):
Each parameter in its Chinese style (IIz) has this paper, preceding text and implication hereinafter described.In certain embodiments, G is C (O) O and can be represented by formula as follows (IIIa)
Each parameter in its Chinese style (IIIa) has this paper, preceding text and implication hereinafter described.
In certain embodiments, compound is a formula (IIz) or (IIIa) and R
24For according to circumstances by 1 to 5 substituted C of substituting group that is selected from the group that forms by following group
1-8Alkyl, C
3-7Naphthenic base, phenyl or heteroaryl: C
1-5Acyl group, C
1-5Acyloxy, C
1-4Alkoxyl group, C
1-7Alkyl, C
1-4Alkylamino, C
1-4Alkyl carboxamide groups, C
1-4Alkylthio carboxamide groups, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, C
1-4Alkylthio urea groups, C
1-4Alkyl urea groups, amino, carbonyl-C
1-6-alkoxyl group, carboxamide groups, carboxyl, cyanic acid, C
3-6-naphthenic base, C
2-8Dialkyl amido, C
2-6Dialkyl group carboxamide groups, C
2-6Two alkylthio carboxamide groups, C
2-6Dialkyl group sulfoamido, C
1-4Alkylthio urea groups, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, C
1-4Alkylhalide group sulfinyl, C
1-4Alkylhalide group alkylsulfonyl, C
1-4Alkylhalide group, C
1-4Alkyl halide sulfenyl, halogen, hydroxyl, hydroxyl amino and nitro.
In certain embodiments, compound is a formula (IIz) or (IIIa) and R
24For according to circumstances by 1 to 5 substituted C of substituting group that is selected from the group that forms by following group
1-8Alkyl, C
1-5Acyl group, C
1-5Acyloxy, C
1-4Alkoxyl group, C
1-7Alkyl, C
1-4Alkylamino, C
1-4Alkyl carboxamide groups, C
1-4Alkylthio carboxamide groups, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, C
1-4Alkylthio urea groups, C
1-4Alkyl urea groups, amino, carbonyl-C
1-6-alkoxyl group, carboxamide groups, carboxyl, cyanic acid, C
3-6-naphthenic base, C
2-8Dialkyl amido, C
2-6Dialkyl group carboxamide groups, C
2-6Two alkylthio carboxamide groups, C
2-6Dialkyl group sulfoamido, C
1-4Alkylthio urea groups, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, C
1-4Alkylhalide group sulfinyl, C
1-4Alkylhalide group alkylsulfonyl, C
1-4Alkylhalide group, C
1-4Alkyl halide sulfenyl, halogen, hydroxyl, hydroxyl amino and nitro.
In certain embodiments, compound is a formula (IIz) or (IIIa) and R
24For according to circumstances by 1 to 5 substituted phenyl C of substituting group that is selected from the group that forms by following group
1-5Acyl group, C
1-5Acyloxy, C
1-4Alkoxyl group, C
1-7Alkyl, C
1-4Alkylamino, C
1-4Alkyl carboxamide groups, C
1-4Alkylthio carboxamide groups, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, C
1-4Alkylthio urea groups, C
1-4Alkyl urea groups, amino, carbonyl-C
1-6-alkoxyl group, carboxamide groups, carboxyl, cyanic acid, C
3-6-naphthenic base, C
2-8Dialkyl amido, C
2-6Dialkyl group carboxamide groups, C
2-6Two alkylthio carboxamide groups, C
2-6Dialkyl group sulfoamido, C
1-4Alkylthio urea groups, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, C
1-4Alkylhalide group sulfinyl, C
1-4Alkylhalide group alkylsulfonyl, C
1-4Alkylhalide group, C
1-4Alkyl halide sulfenyl, halogen, hydroxyl, hydroxyl amino and nitro.In certain embodiments, phenyl is replaced by 1 to 4 substituting group that is selected from the group that is made up of following group: C
1-5Acyl group, C
1-4Alkoxyl group, C
1-7Alkyl, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, carboxamide groups, carboxyl, C
3-7Naphthenic base, C
2-8Dialkyl amido, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, C
1-4Alkylhalide group sulfinyl, C
1-4Alkylhalide group alkylsulfonyl, C
1-4Alkylhalide group, C
1-4Alkyl halide sulfenyl and halogen.In certain embodiments, phenyl is selected from by C by 1 to 4
1-4Alkyl sulphonyl, C
1-4The substituting group of the group that alkylhalide group alkylsulfonyl and halogen are formed replaces.
In certain embodiments, compound is a formula (IIz) or (IIIa) and R
24For according to circumstances by 1 to 5 the substituted heteroaryl of substituting group that is selected from the group that forms by following group: C
1-5Acyl group, C
1-5Acyloxy, C
1-4Alkoxyl group, C
1-7Alkyl, C
1-4Alkylamino, C
1-4Alkyl carboxamide groups, C
1-4Alkylthio carboxamide groups, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, C
1-4Alkylthio urea groups, C
1-4Alkyl urea groups, amino, carbonyl-C
1-6-alkoxyl group, carboxamide groups, carboxyl, cyanic acid, C
3-6-naphthenic base, C
2-8Dialkyl amido, C
2-6Dialkyl group carboxamide groups, C
2-6Two alkylthio carboxamide groups, C
2-6Dialkyl group sulfoamido, C
1-4The alkylthio urea groups, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, C
1-4Alkylhalide group sulfinyl, C
1-4Alkylhalide group alkylsulfonyl, C
1-4Alkylhalide group, C
1-4Alkyl halide sulfenyl, halogen, hydroxyl, hydroxyl amino and nitro.In certain embodiments, heteroaryl is replaced by 1 to 4 substituting group that is selected from the group that is made up of following group: C
1-5Acyl group, C
1-4Alkoxyl group, C
1-7Alkyl, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, carboxamide groups, carboxyl, C
3-7Naphthenic base, C
2-8Dialkyl amido, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, C
1-4Alkylhalide group sulfinyl, C
1-4Alkylhalide group alkylsulfonyl, C
1-4Alkylhalide group, C
1-4Alkyl halide sulfenyl and halogen.In certain embodiments, heteroaryl is selected from by C by 1 to 4
1-4Alkyl sulphonyl, C
1-4The substituting group of the group that alkylhalide group alkylsulfonyl and halogen are formed replaces.In certain embodiments, heteroaryl is the 5-shown in a preceding text table 2A unit heteroaryl for example.In certain embodiments, heteroaryl is the 6-shown in the preceding text table 4 a unit heteroaryl for example.In certain embodiments, heteroaryl is selected from the group that is made up of pyridyl, pyridazinyl, pyrimidyl and pyrazinyl.In certain embodiments, heteroaryl is a pyridyl.
In certain embodiments, R
24Be 1-methyl isophthalic acid H-imidazol-4 yl or 2,4-dimethyl--thiazole-5-base.
In certain embodiments, compound be formula (IIy), (IIx) or (IIIa) and Q be NR
4, O, S, S (O) or S (O)
2In other embodiments, Q is NH or O.
Some embodiments of the invention are about Ar wherein
1For according to circumstances by R
13, R
14, R
15, R
16And R
17The compound of substituted aryl or heteroaryl;
R wherein
13Be selected from the group that forms by following group: C
1-6Acyl group sulfoamido, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkylamino, C
1-6Alkyl carboxamide groups, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, amino, carbamyl imino-, carboxamide groups, carboxyl, cyanic acid, C
2-6Dialkyl amido, halogen, heterocyclic radical, heterocyclic radical-oxygen base, heterocyclic radical-carbonyl, heteroaryl, heteroaryl carbonyl and sulfoamido, and wherein said C
1-6Aryl-sulfonyl amino, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkylamino, C
1-4Alkylsulfonamido, alkyl sulphonyl, C
1-4Alkylthio, carbamyl imino-, C
2-6Dialkyl amido, heterocyclic radical, heterocyclic radical-carbonyl and heteroaryl are replaced by 1 to 5 substituting group that independently is selected from the group that is made up of following group separately according to circumstances: C
1-6Acyl group sulfoamido, C
1-4Alkoxyl group, C
1-7Alkyl, C
1-4Alkyl carboxamide groups, C
1-4Alkyl sulphonyl, carboxyl, C
3-7Cycloalkyloxy, C
2-6Dialkyl amido, C
2-6Dialkyl group carboxamide groups, heteroaryl, heterocyclic radical, hydroxyl, phenyl and phosphonato, wherein said C
1-7Alkyl and C
1-4The alkyl carboxamide groups is selected from by C by 1 to 5 separately according to circumstances
1-4The substituting group of the group that alkoxyl group and hydroxyl are formed replaces; And
R
14, R
15, R
16And R
17Independently be selected from the group that forms by following group: C separately
1-6Acyl group sulfoamido, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkylamino, C
1-4Alkyl carboxamide groups, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, amino, carbamyl imino-, carboxamide groups, cyanic acid, C
2-6Dialkyl amido and halogen.
Some embodiments of the invention are about Ar wherein
1Compound for aryl.
Some embodiments of the invention are about Ar wherein
1Compound for heteroaryl.
Some embodiments of the invention are about Ar wherein
1For according to circumstances by R
13, R
14, R
15, R
16And R
17The compound of substituted phenyl;
R wherein
13Be selected from the group that forms by following group: C
1-6Acyl group sulfoamido, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkylamino, C
1-6Alkyl carboxamide groups, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, amino, carbamyl imino-, carboxamide groups, carboxyl, cyanic acid, C
2-6Dialkyl amido, C
1-4Alkylhalide group, halogen, heterocyclic radical, heterocyclic radical-oxygen base, heterocyclic radical-carbonyl, heteroaryl, heteroaryl carbonyl and sulfoamido, and C wherein
1-6Acyl group sulfoamido, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkylamino, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, carbamyl imino-, C
2-6Dialkyl amido, heterocyclic radical, heterocyclic radical-carbonyl and heteroaryl are replaced by 1 to 5 substituting group that independently is selected from the group that is made up of following group separately according to circumstances: C
1-6Acyl group sulfoamido, C
1-4Alkoxyl group, C
1-7Alkyl, C
1-4Alkyl carboxamide groups, C
1-4Alkyl sulphonyl, carboxyl, C
3-7Cycloalkyloxy, C
2-6Dialkyl amido, C
2-6Dialkyl group carboxamide groups, heteroaryl, heterocyclic radical, hydroxyl, phenyl and phosphonato, wherein said C
1-7Alkyl and C
1-4The alkyl carboxamide groups is selected from by C by 1 to 5 according to circumstances
1-4The substituting group of the group that alkoxyl group and hydroxyl are formed replaces; And
R
14, R
15, R
16And R
17Independently be selected from the group that forms by following group: C separately
1-6Acyl group sulfoamido, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkylamino, C
1-4Alkyl carboxamide groups, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, amino, carbamyl imino-, carboxamide groups, cyanic acid, C
2-6Dialkyl amido, C
1-4Alkylhalide group and halogen.
Some embodiments of the invention are about compound, wherein Ar
1For according to circumstances by R
13, R
14, R
15, R
16And R
17Substituted phenyl;
R wherein
13Be selected from the group that forms by following group: C
1-6Acyl group sulfoamido, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkylamino, C
1-6Alkyl carboxamide groups, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, carbamyl imino-, carboxamide groups, carboxyl, cyanic acid, C
2-6Dialkyl amido, halogen, heterocyclic radical, heterocyclic radical-oxygen base, heterocyclic radical-carbonyl, heteroaryl, heteroaryl carbonyl and sulfoamido, and C wherein
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkylamino, C
1-6Alkyl carboxamide groups, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, carbamyl imino-, C
2-6Dialkyl amido, heterocyclic radical, heterocyclic radical-carbonyl and heteroaryl are replaced by 1 to 5 substituting group that independently is selected from the group that is made up of following group separately according to circumstances: C
1-6Acyl group sulfoamido, C
1-4Alkoxyl group, C
1-7Alkyl, C
1-4Alkyl carboxamide groups, C
1-4Alkyl sulphonyl, carboxyl, C
2-6Dialkyl amido, C
2-6Dialkyl group carboxamide groups, heteroaryl, heterocyclic radical, hydroxyl, phenyl and phosphonato, wherein said C
1-7Alkyl and C
1-4The alkyl carboxamide groups is selected from by C by 1 to 5 according to circumstances
1-4The substituting group of the group that alkoxyl group and hydroxyl are formed replaces, and
R
14, R
15, R
16And R
17Independently be selected from the group that forms by following group: C separately
1-6Acyl group sulfoamido, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkylamino, C
1-4Alkyl carboxamide groups, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, amino, carbamyl imino-, carboxamide groups, cyanic acid, C
2-6Dialkyl amido and halogen.
Some embodiments of the invention are about compound, wherein Ar
1For according to circumstances by R
13, R
14, R
15, R
16And R
17Substituted phenyl;
R wherein
13Be selected from the group that forms by following group: C
1-4Acyl group sulfoamido, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkylamino, C
1-6Alkyl carboxamide groups, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, carbamyl imino-, carboxamide groups, carboxyl, cyanic acid, C
2-6Dialkyl amido, halogen, heterocyclic radical, heterocyclic radical-oxygen base, heterocyclic radical-carbonyl, heteroaryl, heteroaryl carbonyl and sulfoamido, and wherein said C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkylamino, C
1-6Alkyl carboxamide groups, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, carbamyl imino-, C
2-6Dialkyl amido, heterocyclic radical, heterocyclic radical-carbonyl and heteroaryl are replaced by 1 to 5 substituting group that independently is selected from the group that is made up of following group separately according to circumstances: C
1-6Acyl group sulfoamido, C
1-4Alkoxyl group, C
1-7Alkyl, C
1-4Alkyl carboxamide groups, C
1-4Alkyl sulphonyl, carboxyl, C
2-6Dialkyl amido, C
2-6Dialkyl group carboxamide groups, heteroaryl, heterocyclic radical, hydroxyl, phenyl and phosphonato, wherein said C
1-7Alkyl and C
1-4The alkyl carboxamide groups is selected from by C by 1 to 5 according to circumstances
1-4The substituting group of the group that alkoxyl group and hydroxyl are formed replaces; And
R
14, R
15, R
16, and R
17Independently be selected from separately by C
1-8The group that alkyl and halogen are formed.
Some embodiments of the invention are about Ar wherein
1Compound for phenyl.In certain embodiments, phenyl is according to circumstances by R
13Replace.In certain embodiments, R
13Be selected from the group that forms by following group: H, C
1-5Acyl group, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkyl carboxamide groups, C
2-6Alkynyl, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, carboxamide groups, C
3-7Naphthenic base, halogen and sulfoamido.
In certain embodiments, R
13Be selected from the group that forms by following group: C (O) CH
3, C (O) CH
2CH
3, C (O) CH
2CH
2CH
3, C (O) CH (CH
3)
2, C (O) CH
2CH
2CH
2CH
3, OCH
3, OCH
2CH
3, OCH
2CH
2CH
3, OCH (CH
3)
2, OCH
2CH
2CH
2CH
3, CH
3, CH
2CH
3, CH
2CH
2CH
3, CH (CH
3)
2, CH (CH
3) (CH
2CH
3), CH
2(CH
2)
2CH
3, CH
2(CH
2)
3CH
3, CH
2(CH
2)
4CH
3, CH
2(CH
2)
5CH
3, C (O) NHCH
3, C (O) NHCH
2CH
3, C (O) NHCH
2CH
2CH
3, C (O) NHCH (CH
3), C (O) NHCH
2(CH
2)
2CH
3, CCH, S (O)
2NHCH
3, S (O)
2NHCH
2CH
3, S (O)
2NHCH
2CH
2CH
3, S (O)
2NHCH (CH
3)
2, S (O)
2NHCH
2(CH
2)
2CH
3And S (O)
2NHCH (CH
3) CH
2CH
3
In certain embodiments, R
13Be selected from the group that forms by following group: S (O) CH
3S (O) CH
2CH
3, S (O) CH
2CH
2CH
3, S (O) CH (CH
3)
2, S (O) CH
2(CH
2)
2CH
3, S (O) CH (CH
3) CH
2CH
3, S (O)
2CH
3, S (O)
2CH
2CH
3, S (O)
2CH
2CH
2CH
3, S (O)
2CH (CH
3)
2, S (O)
2CH
2(CH
2)
2CH
3, S (O)
2CH (CH
3) CH
2CH
3, SCH
3, SCH
2CH
3, SCH
2CH
2CH
3, SCH (CH
3)
2And SCH
2(CH
2)
2CH
3
In certain embodiments, R
13Be selected from the group that forms by following group: amino, aryl sulfonyl, carboxyl, cyanic acid, C
3-7Naphthenic base, halogen, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group and C
1-4The alkyl halide sulfenyl.In certain embodiments, R
13Be selected from the group that forms by following group: benzenesulfonyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Cl, F, Br, OCF
3, OCHF
2, OCH
2CF
3, CF
3, CHF
2, CH
2CF
3, SCF
3, SCHF
2And SCH
2CF
3In certain embodiments, R
13Be selected from by heterocyclic radical, heteroaryl, C
4-7The group that ketone group-naphthenic base, phenoxy and phenyl are formed.In certain embodiments, R
13Be selected from the group that forms by following group: morpholine-4-base, thiomorpholine-4-base, 1-ketone group-1 λ
4-thiomorpholine-4-base, 1,1-diketo-1 λ
6-thiomorpholine-4-base, piperazine-1-base, 4-methyl-piperazine-1-base, 4-ethyl-piperazine-1-base, 4-propyl group-piperazine-1-base, piperidines-1-base, tetramethyleneimine-1-base, 2; 5-diketo-imidazolidine-4-base, 2; 4-diketo-thiazolidine-5-base, 4-ketone group-2-sulfenyl-thiazolidine-5-base, 3-methyl-2; 5-diketo-imidazolidine-4-base, 3-methyl-2; 4-diketo-thiazolidine-5-base, 3-methyl-4-ketone group-2-sulfenyl-thiazolidine-5-base, 3-ethyl-2,5-diketo-imidazolidine-4-base, 3-ethyl-2,4-diketo-thiazolidine-5-base and 3-ethyl-4-ketone group-2-sulfenyl-thiazolidine-5-base.In certain embodiments, R
13Be selected from the group that forms by following group: 1H-imidazol-4 yl, [1,2,4] triazol-1-yl, [1,2; 3] triazol-1-yl, [1,2,4] triazole-4-base, pyrroles-1-base, pyrazol-1-yl, 1H-pyrazole-3-yl, imidazoles-1-Ji 、 oxazole-5-Ji 、 oxazole-2-base, [1,3; 4] oxadiazole-2-base, [1,3,4] thiadiazoles-2-base, [1,2; 4] oxadiazole-3-base, [1,2,4] thiadiazoles-3-base, tetrazolium-1-base, pyrimidine-5-base, pyrimidine-2-base, pyrimidine-4-base, pyridazine-3-base, pyridazine-4-base, pyrazine-2-base, 1,3-diketo-1; 3-dihydro-isoindole-2-base and [1,2,3] thiadiazoles-4-base.In certain embodiments, R
13For according to circumstances by 1 to 5 substituted C of substituting group that independently is selected from the group that forms by following group
1-8Alkyl or C
1-4Alkoxyl group: C
1-4Alkoxyl group, C
1-4Alkyl carboxamide groups, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, carbonyl-C
1-6-alkoxyl group, carboxamide groups, carboxyl, cyanic acid, heterocyclic radical, hydroxyl and phenyl.In certain embodiments, R
13For according to circumstances by 1 to 5 substituted C of substituting group that independently is selected from the group that forms by following group
1-4Alkyl sulphonyl: C
1-4Alkoxyl group, carboxamide groups, heteroaryl, heterocyclic radical and phenyl.In certain embodiments, C
1-4Alkyl sulphonyl is replaced by heteroaryl.In certain embodiments, heteroaryl is selected from the group that is made up of following group: 1H-imidazol-4 yl, [1,2,4] triazol-1-yl, [1; 2,3] triazol-1-yl, [1,2,4] triazole-4-base, pyrroles-1-base, pyrazol-1-yl, 1H-pyrazole-3-yl, imidazoles-1-Ji 、 oxazole-5-Ji 、 oxazole-2-base, [1; 3,4] oxadiazole-2-base, [1,3,4] thiadiazoles-2-base, [1; 2,4] oxadiazole-3-base, [1,2,4] thiadiazoles-3-base, tetrazolium-1-base, pyrimidine-5-base, pyrimidine-2-base, pyrimidine-4-base, pyridazine-3-base, pyridazine-4-base, pyrazine-2-base, 1; 3-diketo-1,3-dihydro-isoindole-2-base and [1,2,3] thiadiazoles-4-base.In certain embodiments, R
13For according to circumstances by 1 to 5 the substituted aryl sulfonyl of substituting group, heteroaryl, phenoxy or phenyl: C that independently is selected from the group that forms by following group
1-5Acyl group, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, carboxamide groups, carboxyl, cyanic acid, halogen, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, C
1-4Alkyl halide sulfenyl and hydroxyl.In certain embodiments, R
13For independently being selected from by 1 to 5 according to circumstances by C
1-4Alkoxyl group, C
1-8Alkyl, cyanic acid, halogen, C
1-4Halogen alkoxyl group, C
1-4The substituted aryl sulfonyl of the substituting group of the group that alkylhalide group and hydroxyl are formed, heteroaryl, phenoxy or phenyl.
Some embodiments of the invention are about Ar wherein
1Compound for phenyl.In certain embodiments, phenyl is according to circumstances by R
13Replace.In certain embodiments, R
13Be formula (A) group
Wherein:
" p " and " r " independently is 0,1,2 or 3; And R
18Be H, C
1-5Acyl group, C
2-6Thiazolinyl, C
1-8Alkyl, C
1-4Alkyl carboxamide groups, C
2-6Alkynyl, C
1-4Alkylsulfonamido, carbonyl-C
1-6-alkoxyl group, carboxamide groups, carboxyl, cyanic acid, C
3-7Naphthenic base, C
2-6Dialkyl group carboxamide groups, halogen, heteroaryl or phenyl, and wherein heteroaryl or phenyl can independently be selected from by C by 1 to 5 according to circumstances
1-4Alkoxyl group, amino, C
1-4Alkylamino, C
2-6Alkynyl, C
2-8Dialkyl amido, halogen, C
1-4Halogen alkoxyl group, C
1-4The substituting group of the group that alkylhalide group and hydroxyl are formed replaces.In certain embodiments, p=0 and r=0.In certain embodiments, R
18For according to circumstances by 1 to 5 substituted heteroaryl of substituting group or phenyl: C that independently is selected from the group that forms by following group
1-4Alkoxyl group, amino, C
1-4Alkylamino, C
2-6Alkynyl, C
2-8Dialkyl amido, halogen, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group and hydroxyl.In certain embodiments, heteroaryl is selected from the group that is made up of following group: 1H-imidazol-4 yl, [1,2,4] triazol-1-yl, [1; 2,3] triazol-1-yl, [1,2,4] triazole-4-base, pyrroles-1-base, pyrazol-1-yl, 1H-pyrazole-3-yl, imidazoles-1-Ji 、 oxazole-5-Ji 、 oxazole-2-base, [1; 3,4] oxadiazole-2-base, [1,3,4] thiadiazoles-2-base, [1; 2,4] oxadiazole-3-base, [1,2,4] thiadiazoles-3-base, tetrazolium-1-base, pyrimidine-5-base, pyrimidine-2-base, pyrimidine-4-base, pyridazine-3-base, pyridazine-4-base, pyrazine-2-base, 1; 3-diketo-1,3-dihydro-isoindole-2-base and [1,2,3] thiadiazoles-4-base.In certain embodiments, p=0 and r=1.In certain embodiments, R
18Be carbonyl-C
1-6-alkoxyl group or carboxyl.In certain embodiments, p=2 and r=1.In certain embodiments, R
18Be H, C
1-5Acyl group or C
1-8Alkyl.
Some embodiments of the invention are about Ar wherein
1Compound for phenyl.In certain embodiments, Ar
1For according to circumstances by R
14, R
15, R
16And R
17Substituted phenyl.In certain embodiments, R
14, R
15, R
16And R
17Independently be selected from the group that forms by following group: H, C
1-5Acyl group, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkyl carboxamide groups, C
1-4Alkyl urea groups, carbonyl-C
1-6-alkoxyl group, carboxamide groups, carboxyl, cyanic acid, C
3-7Naphthenic base, halogen, C
1-4Halogen alkoxyl group and C
1-4Alkylhalide group.In certain embodiments, R
14, R
15, R
16And R
17Be halogen.In another embodiment, said halogen is a fluorine atom.
Some embodiments of the invention are about compound, wherein Ar
1Be phenyl and R
13In the phenyl contraposition, be substituted; Said embodiment can be represented by formula as follows (IIIc).
Each parameter in its Chinese style (IIIc) has this paper, preceding text and implication hereinafter described.
Some embodiments of the invention are about compound, wherein Ar
1Be phenyl and two adjacent R
14, R
15, R
16And R
17Form and phenyl condensed 5,6 or 7 yuan of naphthenic base, cycloalkenyl group or heterocyclic radicals with the atom that is connected with them, wherein 5,6 or 7 yuan of groups are replaced by halogen according to circumstances.In certain embodiments, phenyl and two adjacent R
14, R
15, R
16And R
17Group forms 5,6 or 7 yuan of condensed ring alkyl as shown in table 5:
Table 5
Wherein " a " is 1,2 or 3 to produce and 5,6 or 7 yuan of naphthenic base of said phenyl condensed shared two ring carbon atoms between wherein said naphthenic base and the phenyl.In certain embodiments, 1,2 or 3 carbon atom is selected from the heteroatoms displacement of (non-limiting) O, S and N, and wherein N is by H or C
1-4Alkyl replaces.In certain embodiments, said two adjacent groups and phenyl form 5 yuan of heterocyclic radicals.In certain embodiments, 5 yuan of heterocyclic radicals are 2 with phenyl, 3-dihydro-cumarone-5-base or benzo [1,3] benzodioxoles-5-base.In certain embodiments, said two adjacent groups and phenyl form 6 yuan of heterocyclic radicals.In certain embodiments, 6 yuan of heterocyclic radicals are 2 with phenyl, 3-dihydro-benzo [1,4] dioxane-6-base or 2,3-dihydro-benzo [1,4] dioxane-2-base.In certain embodiments, said two adjacent groups and phenyl form 7 yuan of heterocyclic radicals.In certain embodiments, 7 yuan of heterocyclic radicals are 3 with phenyl, 4-dihydro-2H-benzo [b] [1,4] dioxa Zhuo-7-base.
Some embodiments of the invention are about compound, wherein Ar
1For according to circumstances by R
13, R
14, R
15And R
16Substituted pyridyl;
R wherein
13Be selected from the group that forms by following group: C
1-6Acyl group sulfoamido, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkylamino, C
1-6Alkyl carboxamide groups, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, amino, carbamyl imino-, carboxamide groups, carboxyl, cyanic acid, C
2-6Dialkyl amido, halogen, heterocyclic radical, heterocyclic radical-oxygen base, heterocyclic radical-carbonyl, heteroaryl and sulfoamido, and C wherein
1-6Acyl group sulfoamido, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkylamino, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, carbamyl imino-, C
2-6Dialkyl amido, heterocyclic radical, heterocyclic radical-carbonyl and heteroaryl are replaced by 1 to 5 substituting group that independently is selected from the group that is made up of following group separately according to circumstances: C
1-6Acyl group sulfoamido, C
1-4Alkoxyl group, C
1-7Alkyl, C
1-4Alkyl carboxamide groups, C
1-4Alkyl sulphonyl, carboxyl, C
3-7Cycloalkyloxy, C
2-6Dialkyl amido, C
2-6Dialkyl group carboxamide groups, heteroaryl, heterocyclic radical, hydroxyl, phenyl and phosphonato, wherein said C
1-7Alkyl and C
1-4The alkyl carboxamide groups is selected from by C by 1 to 5 according to circumstances
1-4The substituting group of the group that alkoxyl group and hydroxyl are formed replaces; And
R
14, R
15And R
16Independently be selected from the group that forms by following group: C separately
1-6Acyl group sulfoamido, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkylamino, C
1-4Alkyl carboxamide groups, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, amino, carbamyl imino-, carboxamide groups, cyanic acid, C
2-6Dialkyl amido and halogen.
Some embodiments of the invention are about compound, wherein Ar
1For according to circumstances by R
13, R
14, R
15And R
16Substituted pyridyl,
R wherein
13Be selected from the group that forms by following group: C
1-6Acyl group sulfoamido, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkylamino, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, amino, C
2-6Dialkyl amido, halogen, heterocyclic radical and sulfoamido, and C wherein
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkylamino, alkyl sulphonyl, C
1-4Alkylthio, C
2-6Dialkyl amido and heterocyclic radical are replaced by 1 to 5 substituting group that independently is selected from the group that is made up of following group separately according to circumstances: C
1-6Acyl group sulfoamido, C
1-4Alkoxyl group, C
1-4Alkyl sulphonyl, C
3-7Cycloalkyloxy, heteroaryl, hydroxyl, phenyl and phosphonato; And
R
14, R
15And R
16Independently be selected from the group that forms by following group: C separately
1-6Acyl group sulfoamido, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkylamino, C
1-4Alkyl carboxamide groups, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, amino, carbamyl imino-, carboxamide groups, cyanic acid, C
2-6Dialkyl amido and halogen.
Some embodiments of the invention are about compound, wherein Ar
1For according to circumstances by R
13, R
14, R
15And R
16Substituted pyridyl;
R wherein
13Be selected from the group that forms by following group: C
1-6Acyl group sulfoamido, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkylamino, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, amino, C
2-6Dialkyl amido, halogen, heterocyclic radical and sulfoamido, and C wherein
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkylamino, alkyl sulphonyl, C
1-4Alkylthio, C
2-6Dialkyl amido and heterocyclic radical are replaced by 1 to 5 substituting group that independently is selected from the group that is made up of following group separately according to circumstances: C
1-6Acyl group sulfoamido, C
1-4Alkoxyl group, C
1-4Alkyl sulphonyl, C
3-7Cycloalkyloxy, heteroaryl, hydroxyl, phenyl and phosphonato; And
R
14, R
15And R
16Independently be selected from separately by C
1-8The group that alkyl and halogen are formed.
Some embodiments of the invention are about formula as follows (IIId) compound
Each parameter in its Chinese style (IIId) has this paper, preceding text and implication hereinafter described.
Some embodiments of the invention are about formula as follows (IIId-1) and (IIId-2) compound
Its Chinese style (IIId-1) and (IIId-2) in each parameter have this paper, preceding text and implication hereinafter described.
Some embodiments of the invention are about Ar wherein
1Compound for heteroaryl.In certain embodiments, heteroaryl is according to circumstances by R
13Replace.In certain embodiments, R
13Be selected from the group that forms by following group: H, C
1-5Acyl group, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkyl carboxamide groups, C
2-6Alkynyl, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, carboxamide groups, C
3-7Naphthenic base, halogen and sulfoamido.In certain embodiments, R
13Be selected from the group that forms by following group: C (O) CH
3, C (O) CH
2CH
3, C (O) CH
2CH
2CH
3, C (O) CH (CH
3)
2, C (O) CH
2CH
2CH
2CH
3, OCH
3, OCH
2CH
3, OCH
2CH
2CH
3, OCH (CH
3)
2, OCH
2CH
2CH
2CH
3, CH
3, CH
2CH
3, CH
2CH
2CH
3, CH (CH
3)
2, CH (CH
3) (CH
2CH
3), CH
2(CH
2)
2CH
3, CH
2(CH
2)
3CH
3, CH
2(CH
2)
4CH
3, CH
2(CH
2)
5CH
3, C (O) NHCH
3, C (O) NHCH
2CH
3, C (O) NHCH
2CH
2CH
3, C (O) NHCH (CH
3)
2, C (O) NHCH
2(CH
2)
2CH
3, CCH, S (O)
2NHCH
3, S (O)
2NHCH
2CH
3, S (O)
2NHCH
2CH
2CH
3, S (O)
2NHCH (CH
3)
2, S (O)
2NHCH
2(CH
2)
2CH
3And S (O)
2NHCH (CH
3) CH
2CH
3
In certain embodiments, R
13Be selected from the group that forms by following group: S (O) CH
3S (O) CH
2CH
3, S (O) CH
2CH
2CH
3, S (O) CH (CH
3)
2, S (O) CH
2(CH
2)
2CH
3, S (O) CH (CH
3) CH
2CH
3, S (O)
2CH
3, S (O)
2CH
2CH
3, S (O)
2CH
2CH
2CH
3, S (O)
2CH (CH
3)
2, S (O)
2CH
2(CH
2)
2CH
3, S (O)
2CH (CH
3) CH
2CH
3, SCH
3, SCH
2CH
3, SCH
2CH
2CH
3, SCH (CH
3)
2And SCH
2(CH
2)
2CH
3
In certain embodiments, R
13Be selected from the group that forms by following group: amino, aryl sulfonyl, carboxyl, cyanic acid, C
3-7Naphthenic base, halogen, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group and C
1-4The alkyl halide sulfenyl.In certain embodiments, R
13Be selected from the group that forms by following group: benzenesulfonyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Cl, F, Br, OCF
3, OCHF
2, OCH
2CF
3, CF
3, CHF
2, CH
2CF
3, SCF
3, SCHF
2And SCH
2CF
3In certain embodiments, R
13Be selected from by heterocyclic radical, heteroaryl, C
4-7The group that ketone group-naphthenic base, phenoxy and phenyl are formed.In certain embodiments, R13 is selected from the group that is made up of following group: morpholine-4-base, thiomorpholine-4-base, 1-ketone group-1 λ
4-thiomorpholine-4-base, 1,1-diketo-1 λ
6-thiomorpholine-4-base, piperazine-1-base, 4-methyl-piperazine-1-base, 4-ethyl-piperazine-1-base, 4-propyl group-piperazine-1-base, piperidines-1-base, tetramethyleneimine-1-base, 2; 5-diketo-imidazolidine-4-base, 2; 4-diketo-thiazolidine-5-base, 4-ketone group-2-diketo-thiazolidine-5-base, 3-methyl-2; 5-diketo-imidazolidine-4-base, 3-methyl-2; 4-diketo-thiazolidine-5-base, 3-methyl-4-ketone group-2-diketo-thiazolidine-5-base, 3-ethyl-2,5-diketo-imidazolidine-4-base, 3-ethyl-2,4-diketo-thiazolidine-5-base and 3-ethyl-4-ketone group-2-diketo-thiazolidine-5-base.In certain embodiments, R
13Be selected from the group that forms by following group: 1H-imidazol-4 yl, [1,2,4] triazol-1-yl, [1,2; 3] triazol-1-yl, [1,2,4] triazole 4-base, pyrroles-1-base, pyrazol-1-yl, 1H-pyrazole-3-yl, imidazoles-1-Ji 、 oxazole-5-Ji 、 oxazole-2-base, [1,3; 4] oxadiazole-2-base, [1,3,4] thiadiazoles-2-base, [1,2; 4] oxadiazole-3-base, [1,2,4] thiadiazoles-3-base, tetrazolium-1-base, pyrimidine-5-base, pyrimidine-2-base, pyrimidine-4-base, pyridazine-3-base, pyridazine-4-base, pyrazine-2-base, 1,3-diketo-1; 3-dihydro-isoindole-2-base and [1,2,3] thiadiazoles-4-base.In certain embodiments, R
13For according to circumstances by 1 to 5 substituted C of substituting group that independently is selected from the group that forms by following group
1-8Alkyl or C
1-4Alkoxy C
1-4Alkoxyl group, C
1-4Alkyl carboxamide groups, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, carbonyl-C
1-6-alkoxyl group, carboxamide groups, carboxyl, cyanic acid, heterocyclic radical, hydroxyl and phenyl.In certain embodiments, R
13For according to circumstances by 1 to 5 substituted C of substituting group that independently is selected from the group that forms by following group
1-4Alkyl sulphonyl: C
1-4Alkoxyl group, carboxamide groups, heteroaryl, heterocyclic radical and phenyl.In certain embodiments, C
1-4Alkyl sulphonyl is replaced by heteroaryl.In certain embodiments, heteroaryl is selected from the group that is made up of following group: 1H-imidazol-4 yl, [1,2,4] triazol-1-yl, [1; 2,3] triazol-1-yl, [1,2,4] triazole-4-base, pyrroles-1-base, pyrazol-1-yl, 1H-pyrazole-3-yl, imidazoles-1-Ji 、 oxazole-5-Ji 、 oxazole-2-base, [1; 3,4] oxadiazole-2-base, [1,3,4] thiadiazoles-2-base, [1; 2,4] oxadiazole-3-base, [1,2,4] thiadiazoles-3-base, tetrazolium-1-base, pyrimidine-5-base, pyrimidine-2-base, pyrimidine-4-base, pyridazine-3-base, pyridazine-4-base, pyrazine-2-base, 1; 3-diketo-1,3-dihydro-isoindole-2-base and [1,2,3] thiadiazoles-4-base.In certain embodiments, R
13For according to circumstances by 1 to 5 the substituted aryl sulfonyl of substituting group, heteroaryl, phenoxy or phenyl: C that independently is selected from the group that forms by following group
1-5Acyl group, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, carboxamide groups, carboxyl, cyanic acid, halogen, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, C
1-4Alkyl halide sulfenyl and hydroxyl.In certain embodiments, R
13For independently being selected from by 1 to 5 according to circumstances by C
1-4Alkoxyl group, C
1-4Alkyl, cyanic acid, halogen, C
1-4Halogen alkoxyl group, C
1-4The substituted aryl sulfonyl of the substituting group of the group that alkylhalide group and hydroxyl are formed, heteroaryl, phenoxy or phenyl.
Some embodiments of the invention are about Ar wherein
1Compound for heteroaryl.In certain embodiments, heteroaryl is according to circumstances by R
13Replace.In certain embodiments, R
13Be formula (A):
Wherein
" p " and " r " independently is 0,1,2 or 3, and R
18Be H, C
1-5Acyl group, C
2-6Thiazolinyl, C
1-8Alkyl, C
1-4Alkyl carboxamide groups, C
2-6Alkynyl, C
1-4Alkylsulfonamido, carbonyl-C
1-6-alkoxyl group, carboxamide groups, carboxyl, cyanic acid, C
3-7Naphthenic base, C
2-6Dialkyl group carboxamide groups, halogen, heteroaryl or phenyl, and wherein heteroaryl or phenyl can independently be selected from by C by 1 to 5 according to circumstances
1-4Alkoxyl group, amino, C
1-4Alkylamino, C
2-6Alkynyl, C
2-8Dialkyl amido, halogen, C
1-4Halogen alkoxyl group, C
1-4The substituting group of the group that alkylhalide group and hydroxyl are formed replaces.In certain embodiments, p=0 and r=0.In certain embodiments, R
18For according to circumstances by 1 to 5 substituted heteroaryl of substituting group or phenyl: C that independently is selected from the group that forms by following group
1-4Alkoxyl group, amino, C
1-4Alkylamino, C
2-6Alkynyl, C
28Dialkyl amido, halogen, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group and hydroxyl.In certain embodiments, heteroaryl is selected from the group that is made up of following group: 1H-imidazol-4 yl, [1,2,4] triazol-1-yl, [1,2; 3] triazol-1-yl, [1,2,4] triazole-4-base, pyrroles-1-base, pyrazol-1-yl, 1H-pyrazole-3-yl, imidazoles-1-Ji 、 oxazole-5-Ji 、 oxazole-2-base, [1; 3,4] oxadiazole-2-base, [1,3,4] thiadiazoles-2-base, [1; 2,4] oxadiazole-3-base, [1,2,4] thiadiazoles-3-base, tetrazolium-1-base, pyrimidine-5-base, pyrimidine-2-base, pyrimidine-4-base, pyridazine-3-base, pyridazine-4-base, pyrazine-2-base, 1; 3-diketo-1,3-dihydro-isoindole-2-base and [1,2,3] thiadiazoles-4-base.In certain embodiments, p=0 and r=1.In certain embodiments, R
16Be carbonyl-C
1-6-alkoxyl group or carboxyl.In certain embodiments, p=2 and r=1.In certain embodiments, R
18Be H, C
1-5Acyl group or C
1-8Alkyl.
Some embodiments of the invention are about Ar wherein
1Compound for heteroaryl.In certain embodiments, Ar
1For according to circumstances by R
14, R
15, R
16And R
17Substituted heteroaryl.In certain embodiments, R
14-R
17Independently be selected from the group that forms by following group: H, C
1-5Acyl group, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkyl carboxamide groups, C
1-4Alkyl urea groups, carbonyl-C
1-6-alkoxyl group, carboxamide groups, carboxyl, cyanic acid, C
3-7Naphthenic base, halogen, C
1-4Chimney alkoxyl group and C
1-4Alkylhalide group.In certain embodiments, R
14, R
15, R
16And R
17Be halogen.In another embodiment, said halogen is a fluorine.
Some embodiments of the invention are about Ar wherein
1Compound for heteroaryl.In certain embodiments, heteroaryl is according to circumstances by R
14, R
15R
16And R
17Replace, wherein two adjacent R
14, R
15, R
16And R
17Form and heteroaryl-condensed 5,6 or 7 yuan of naphthenic base, cycloalkenyl group or heterocyclic radicals with the atom that is connected with them, wherein 5,6 or 7 yuan of groups are replaced by halogen according to circumstances.In certain embodiments, said two adjacent groups form and 5 yuan of heteroaryl-condensed heterocyclic radicals.In certain embodiments, said two adjacent groups form and 6 yuan of heteroaryl-condensed heterocyclic radicals.In certain embodiments, said two adjacent groups form and 7 yuan of heteroaryl-condensed heterocyclic radicals.
Some embodiments of the invention are about compound, wherein R
3And R
4Independent is H or CH
3
Some embodiments of the invention are about compound, and wherein M and J are that N (being nitrogen-atoms) and T are CR
5In certain embodiments, Z and U are C (being carbon atom); Said embodiment can be represented by formula as follows (IIIe):
Each parameter in its Chinese style (IIIe) has this paper, preceding text and implication hereinafter described.
Some embodiments of the invention are about compound, and wherein V is a key; Said embodiment is represented by formula as follows (IIIg):
Each parameter in its Chinese style (IIIg) has this paper, preceding text and implication hereinafter described.Some embodiments of the invention are about compound, and wherein W is N.Some embodiments of the invention are about compound, and wherein X is CR
9And Y is CR
10In certain embodiments, V is key and is represented by formula (IIIi):
Each parameter in its Chinese style (IIIi) has this paper, preceding text and implication hereinafter described.W is N (being nitrogen-atoms) in certain embodiments.
Some embodiments of the invention are that N and Y are CR about X wherein
10Compound.In another embodiment, V is key and is represented by formula (IIIk):
Each parameter in its Chinese style (IIIk) has this paper, preceding text and implication hereinafter described.W is N (being nitrogen-atoms) in certain embodiments.
Some embodiments of the invention are about compound, and wherein X is CR
9And Y is N.In certain embodiments, V is key and is represented by formula (IIIm):
Each parameter in its Chinese style (IIIm) has this paper, preceding text and implication hereinafter described.W is N (being nitrogen-atoms) in certain embodiments.
Some embodiments of the invention are about compound, and wherein X and Y are N.In certain embodiments, V is key and is represented by formula (IIIo):
Each parameter in its Chinese style (IIIo) has this paper, preceding text and implication hereinafter described.W is N (being nitrogen-atoms) in certain embodiments.
Some embodiments of the invention are about formula (H7) compound:
Wherein
A is-CH
2-or-CH
2CH
2-;
B is-CH
2-,-CH
2CH
2-or-CH
2CH
2CH
2-;
E is CH:
D is N-R
2
K is-CH
2-,-CH
2CH
2-,-CH (CH
3) CH
2-or key,
Q is O, S, S (O), S (O)
2, NH;
R
5Be H, CH
3Or N (CH
3)
2
R
10Be H or CH
3
R
2For-CR
25R
26C (O) R
24,-C (O) R
24,-C (O) NR
25R
24,-R
24,-C (O) OR
24,-C (S) NR
25R
24Or-CR
25R
26R
24, R wherein
24For according to circumstances by 1 to 5 substituted C of substituting group that independently is selected from the group that forms by following group
1-8Alkyl, C
3-7Naphthenic base, phenyl, heteroaryl or heterocyclic radical: C
2-6Thiazolinyl, C
1-4Alkoxyl group, C
1-7Alkyl, C
1-4Alkyl sulphonyl, amino, carbonyl-C
1-6-alkoxyl group, carboxyl, cyanic acid, C
3-7Naphthenic base, C
2-8Dialkyl amido, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, halogen, heteroaryl, heterocyclic radical, hydroxyl, phenyl, phenoxy and sulfonic acid, wherein said C
1-7Alkyl, phenyl and phenoxy are replaced by 1 to 5 substituting group that is selected from the group that is made up of following group separately according to circumstances: amino, C
1-4Halogen alkoxyl group and heterocyclic radical; And R
25And R
26Independent separately is H or C
1-8Alkyl; And
Ar
1For according to circumstances by R
13, R
14, R
15, R
16And R
17Substituted aryl or heteroaryl; R wherein
13Be selected from the group that forms by following group: C
1-6Acyl group sulfoamido, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkylamino, C
1-6Alkyl carboxamide groups, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, amino, carbamyl imino-, carboxamide groups, carboxyl, cyanic acid, C
2-6Dialkyl amido, halogen, heterocyclic radical, heterocyclic radical-oxygen base, heterocyclic radical-carbonyl, heteroaryl and sulfoamido, and C wherein
1-6Acyl group sulfoamido, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkylamino, C
1-4Alkylsulfonamido, alkyl sulphonyl, C
1-4Alkylthio, carbamyl imino-, C
2-4Each is replaced dialkyl amido, heterocyclic radical, heterocyclic radical-carbonyl and heteroaryl by 1 to 5 substituting group that independently is selected from the group that is made up of following group according to circumstances: C
1-6Acyl group sulfoamido, C
1-4Alkoxyl group, C
1-7Alkyl, C
1-4Alkyl carboxamide groups, C
1-4Alkyl sulphonyl, carboxyl, C
3-7Cycloalkyloxy, C
2-6Dialkyl amido, C
2-6Dialkyl group carboxamide groups, heteroaryl, heterocyclic radical, hydroxyl, phenyl and phosphonato, wherein said C
1-7Alkyl and C
1-4The alkyl carboxamide groups is separately according to circumstances by 1 to 5 free C
1-4The substituting group of the group that alkoxyl group and hydroxyl are formed replaces; And
R
14, R
15, R
16And R
17Independently be selected from the group that forms by following group: C separately
1-6Acyl group sulfoamido, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkylamino, C
1-4Alkyl carboxamide groups, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, amino, carbamyl imino-, carboxamide groups, cyanic acid, C
2-6Dialkyl amido and halogen.
Some embodiments of the invention are about formula (H7) compound:
A and B are-CH
2CH
2-;
E is CH:
is singly-bound.
D is N-R
2
K is a key;
Q is O or NH;
R
5And R
10All be H;
R
2For-C (O) OR
24And R
24For separately according to circumstances by 1 to 5 substituted C of substituting group that is selected from the group that forms by following group
1-8Alkyl or C
3-7Naphthenic base, C
1-4Alkoxyl group, C
1-7Alkyl, C
1-4Alkyl sulphonyl, amino, carbonyl-C
1-6-alkoxyl group, carboxyl, cyanic acid, C
3-7Naphthenic base, C
2-7Dialkyl amido, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, halogen, heteroaryl, heterocyclic radical, hydroxyl, phenyl and phenoxy; And
Ar
1For according to circumstances by R
13, R
14, R
15, R
16And R
17Substituted aryl or heteroaryl; R wherein
13Be selected from the group that forms by following group: C
1-6Acyl group sulfoamido, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkylamino, C
1-6Alkyl carboxamide groups, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, amino, carbamyl imino-, carboxamide groups, carboxyl, cyanic acid, C
2-6Dialkyl amido, halogen, heterocyclic radical, heterocyclic radical-oxygen base, heterocyclic radical-carbonyl, heteroaryl and sulfoamido, and C wherein
1-6Acyl group sulfoamido, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkylamino, C
1-4Alkylsulfonamido, alkyl sulphonyl, C
1-4Alkylthio, carbamyl imino-, C
2-6Dialkyl amido, heterocyclic radical, heterocyclic radical-carbonyl and heteroaryl are replaced by 1 to 5 substituting group that independently is selected from the group that is made up of following group separately according to circumstances: C
1-6Acyl group sulfoamido, C
1-4Alkoxyl group, C
1-7Alkyl, C
1-4Alkyl carboxamide groups, C
1-4Alkyl sulphonyl, carboxyl, C
3-7Cycloalkyloxy, C
2-6Dialkyl amido, C
2-6Dialkyl group carboxamide groups, heteroaryl, heterocyclic radical, hydroxyl, phenyl and phosphonato, wherein said C
1-7Alkyl and C
1-4The alkyl carboxamide groups is selected from by C by 1 to 5 separately according to circumstances
1-4The substituting group of the group that alkoxyl group and hydroxyl are formed replaces, and
R
14, R
15, R
16, and R
17Independently be selected from separately by C
1-4Alkoxyl group, C
1-8The group that alkyl and halogen are formed.
Some embodiments of the invention are about formula (H7) compound
A and B are-CH
2CH
2-;
E is CH;
D is N-R
2,
K is a key;
Q is O or NH;
R
5And R
10All be H;
R
2For-C (O) OR
24R wherein
24Be C
1-8Alkyl or C
3-7Naphthenic base,
Ar
1For according to circumstances by R
13, R
14, R
15, R
16And R
17Substituted phenyl, 3-pyridyl or 2-pyridyl,
R wherein
13Be selected from the group that forms by following group: C
1-6Acyl group sulfoamido, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkylamino, C
1-6Alkyl carboxamide groups, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, carbamyl imino-, carboxamide groups, carboxyl, cyanic acid, C
2-6Dialkyl amido, halogen, heterocyclic radical, heterocyclic radical-oxygen base, heterocyclic radical-carbonyl, heteroaryl, heteroaryl carbonyl and sulfoamido, and C wherein
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkylamino, C
1-6Alkyl carboxamide groups, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, carbamyl imino-, C
2-6Dialkyl amido, heterocyclic radical, heterocyclic radical-carbonyl and heteroaryl are replaced by 1 to 5 substituting group that independently is selected from the group that is made up of following group separately according to circumstances: C
1-6Acyl group sulfoamido, C
1-4Alkoxyl group, C
1-7Alkyl, C
1-4Alkyl carboxamide groups, C
1-4Alkyl sulphonyl, carboxyl, C
2-6Dialkyl amido, C
2-6Dialkyl group carboxamide groups, heteroaryl, heterocyclic radical, hydroxyl, phenyl and phosphonato, wherein said C
1-7Alkyl and C
1-4The alkyl carboxamide groups is selected from by C by 1 to 5 according to circumstances
1-4The substituting group of the group that alkoxyl group and hydroxyl are formed replaces, and
R
14, R
15, R
16And R
17Independent separately is CH
3Or F.
In certain embodiments, R
2Be selected from the group that forms by following group: methoxycarbonyl, ethoxy carbonyl, isopropoxy carbonyl, positive propoxy carbonyl, n-butoxy carbonyl, tert-butoxycarbonyl, isobutoxy carbonyl and n-pentyloxy carbonyl.
In certain embodiments, R
11Be selected from the group that forms by following group:
Sulfamyl [promptly-S (O)
2NH
2];
The ethanoyl sulfamyl [promptly-S (O)
2NHC (O) CH
3],
The propionyl group sulfamyl [promptly-S (O)
2NHC (O) CH
2CH
3],
The butyryl radicals sulfamyl [promptly-S (O)
2NHC (O) CH
2CH
2CH
3];
The pentanoyl sulfamyl [promptly-S (O) NHC (O) CH
2CH
2CH
3];
Methylsulfonyl [promptly-S (O)
2CH
3];
Ethylsulfonyl [promptly-S (O)
2CH
2CH
3];
Third-1-alkylsulfonyl [promptly-S (O)
2CH
2CH
2CH
3];
Methylol (promptly-CH
2OH);
The 2-hydroxyethyl (promptly-CH
2CH
2OH);
The 3-hydroxypropyl (promptly-CH
2CH
2CH
2OH);
4-hydroxyl-butyl (promptly-CH
2CH
2CH
2CH
2OH),
The phosphonato methyl [promptly-CH
2OP (O) (OH)
2];
2-phosphonato-ethyl [promptly-CH
2CH
2OP (O) (OH)
2],
3-phosphonato-propyl group [promptly-CH
2CH
2CH
2OP (O) (OH)
2]; And
4-phosphonato-butyl [promptly-CH
2CH
2CH
2CH
2OP (O) (OH)
2],
The inventor has found and can the various aromatic nucleus that condense be used for the present invention.Said condensed ring system is represented by the ring that parameter G, F, J, U, W, V, X, Y and Z in formula (I) and other formula disclosed herein are indicated.In certain embodiments, said condensed ring is that wherein two annular atomses (being U and Z) are encircled shared 6-6 condensed ring each other by two.In certain embodiments, said condensed ring is that wherein two annular atomses (being U and Z) are encircled shared 6-5 condensed ring each other by two.The representative condensed ring of the present invention includes, but is not limited to disclose in the following table 6.
Table 6
Some embodiments of the invention are about compound, and wherein M, J, X and W are N, and T is CR
5Y is CR
10V is that key and Z and U are C.
Some embodiments of the invention are about compound, and wherein M, J, X and W are N; T is CR
5, R wherein
5For-H ,-CH
3Or-N (CH
3)
2Y is CR
10R wherein
10For-H or-CH
3V is that key and Z and U are C.
Some embodiments of the invention are about compound, and wherein M, J, X and W are N, and T is C-H; Y is C-H; V is that key and Z and U are C.
In some embodiments of the invention, compound is not one or more compounds of explanation in the hereinafter table 7.
Table 7
Some embodiments of the invention are about compound, wherein R
5, R
6, R
7, R
8, R
9And R
10Independently be selected from the group that forms by following group: H, C
1-4Alkoxyl group, C
1-8Alkyl, C
2-6Alkynyl, amino, C
3-7Naphthenic base and C
1-4Alkylhalide group.
In certain embodiments, R
5, R
6, R
7, R
8, R
9And R
10Independent is H or C
1-8Alkyl.
In certain embodiments, R
5, R
6, R
7, R
8, R
9And R
10Independent is H or CH
3
In certain embodiments, R
5Be H.
Some embodiments of the invention are about compound, wherein R
11And R
12Independently be selected from the group that forms by following group: H, C
1-8Alkyl, C
2-6Alkynyl, C
3-7Naphthenic base and C
1-4Alkylhalide group.In certain embodiments, R
11And R
12Independent is H or C
1-8Alkyl.
In certain embodiments, R
11And R
12Independent is H or C
11Alkyl.
In certain embodiments, R
11And R
12Independent is H or CH
3
Some embodiments of the invention comprise the compound that Table A as follows, B, C, D, E, F, G, I, J and K are illustrated.
Table A
Table B
Table C
Table D
Table E
Table F
Table G
Table I
Table J
Table K
Therefore, for example the The compounds of this invention of formula (I) and its relational expression is contained especially hydrate of its all pharmaceutically acceptable salt, solvolyte.
The general method of preparation The compounds of this invention
Can easily prepare compounds of the present invention according to multiple synthetic processing, one of ordinary skill in the art will be familiar with all aforesaid methods.The specific preparation method of The compounds of this invention includes, but is not limited to flow process hereinafter described.
Can suitable nucleophile be used for replace muriate, bromide or triflate from bicyclic heterocycle.Said conversion can under the condition and range of for example heat heating and microwave heating, carry out or can through or without adding other is for example sour, the reagent of alkali or transition metal salt etc. comes catalysis (flow process 1).
Can be through for example with bromine or through carrying out the female heterocycle of the direct halogenation of group bromination reaction with N-bromo-succinimide or through with for example (but being not limited to) POCl
3, PCl
5Or the chlorizating agent of its some combinations handle with oxy-compound (when M=N with or can amide form during J=N exist) change into muriate and come to prepare the most easily bicyclic heterocycle halogenide.
Many bicyclic heterocycles can prepare through using document method said or that adopted.For example, the pyrazolopyrimidine of structure H7 can be prepared as follows (flow process 3) in the table 6.
Use POCl subsequently
3Handle and as indicated abovely carry out the The compounds of this invention that nucleophilic displacement one of can produce among the embodiment with amino or alkoxide nucleophilic reagent.
Similar approach can be used for other and 6,5 condenses system's (flow process 4), and wherein the aminocarboxylic amide derivatives can come condensation with other little carbon plate section.Instance H11 (Bull Chem Soc Jap (1979) 52,208), H12, H13 (Leibigs Am Chim (1979),
10, 1534), H15 (Indian J Chem, SecB (1994); 33B; 436), H49, H50 and H51 (Bioorg Med Chem Lett, (2002), 12; 2133) compound of shown type can respectively pass through said general process, respectively through from through protection pyrazoles, isoxazole, thiazole with thiophene begins and with small molecular weight carboxylic acid, aldehyde or heat cyclisation with triethyl ortho-formiate or diacetyl oxide and prepare (flow process 4).
Other 6,5 annelated heterocycles (for example H6, H8, H9, H10 (referring to WO9749706), H12, H14, H46, H47 and H48) that contain pyrimidine ring also can prepare from suitable amide base amine material through similar route of synthesis.Yet, go up than easier otherwise in some cases 5-unit ring is fused to the first ring of established 6-.For example, the compound of instance H8 and H9 can form (flow process 5) from common intermediate material.
In some said situation, maybe be more useful before accomplishing the ring cyclization with suitable nucleophilic component displacement muriate group.
Can similar approach be used for pyridine synthesis base 2, the 3-annelated heterocycles.For example, can through with suitable malonic ester 28 verivate condensations (Heterocyclic communications, (2000),
6463) flow process 6 from amino-5-unit heterocycle prepare H22 for example heterocycle or as flow process 6b replace N-arylpyrazole formation regional isomerism pyrazolo [4,3-c] pyridine from the aldehyde formula.Can prepare the for example heterocycle of H21, H27 and H28 through similar approach.Can prepare the for example heterocycle (flow process 6) of H25 and H26 through WO9635689 and the described respectively method of WO 01087892.
Flow process 6b
As reacting with annelated pyrimidines base system row, more careful sometimes second formation of 5-unit ring that makes prepares annelated heterocycles.
Can prepare for example heterocycle H23 (WO 01053263) and H24 (WO 9808847) (flow process 7) by general intermediate.
In addition, can be with for example l Med Chem, (2003), 46,4702 said alternative condensation methods are used to prepare the pyridyl furans: if replace alcohol as starting point in mercaptan, can same procedure be used for the H30 that synthetic WO 9847903 also described so.
In addition; Can identical ketone intermediate be used to prepare similar oxime, it can be through being cyclized into pyridyl isoxazole (H27) and pyridyl isothiazole (H28) (flow process 9) respectively with the appropriate acid catalyst treatment of for example Tripyrophosphoric acid or through using acid catalyst and under the Dean-Star condition, heating.
Flow process 9
Especially wherein 5-unit ring is being fused to 6 of 3-pyridyl ring; 5-condenses in some instances of system; Be necessary that the activation loop systems makes it have more reactivity to nucleophilic reagent, for example through pyridyl nitrogen being oxidized to N-oxide compound (Acta Pol Pharm (1984) for example
41, 601) form suitable intermediate and form heterocycle H38 and H39 (flow process 10).
Perhaps, can come advantageously to use nitrogen position described in some instances for the locational nucleophilic reaction of the 4-of nitrogen, for example can pass through nucleophilic reaction through wild phase, then cyclization prepare H41 (J Mol Structure, (1987),
158, 99), maybe can prepare H42 through following cyclization with the azanol condensation, this is a kind of by the nitrogen enhanced method (flow process 11) that exists in the pyridine ring position.
Flow process 11
This and Several Methods mentioned above combination, can prepare a large amount of 6,5-condensed-bicyclic template.In each situation, said template is used for proper group Ar
1Be oriented to correct direction with central position Q-K-(EBDA) on every side and make the biological activity maximization.The also available same way as of said proper group is arranged in 6, around the 6-condensed-bicyclic nuclear.In fact, can be according to being similar to preparation 6, the method that the 5-annelated pyrimidines is adopted prepares 6 from condensation arylamino carboxamide derivative, the 6-annelated pyrimidines, promptly said pyrimidine ring can second formation.
In this way can by suitable through substituted-phenyl or heterocyclic ring prepare H1 (referring to Tetrahedron (2000), 56,5499, J Am Chem Soc (2002),
1241594), H2 (WO 0202549), H3 (WO 980820), H4 and H5 (Montash fur Chenue, (1978)
109, 527).
Flow process 12
In another embodiment, said pyrimidine ring can be aryl Ar
1Connected dicyclo component; Wherein said loop systems can be by suitable EL-970 base aryl ketones intermediate (wherein M or T=N) preparation, and this is a process that forms pyrimidine ring through the intramolecular cyclization process by the suitable leaving group R of the formed amino part nucleophilic displacement of oxime of (for example) reduction precursor ketone.Chlorination gained class urea intermediate is also followed the desired loop systems of reduction generation (JHeterocyclic Chem, (1989)
26105) (flow process 13).
Flow process 13
One of them 6-unit ring is 6 of a 2-pyrimidine-ring, and 6-condenses material, and it also can be through on the amino substituted-phenyl or heterocyclic radical that the suitable construction unit are fused to existence, for example
Flow process 14
In said mode, can prepare H16 (Yakugaku Zasshi (1987)
107, 123), the heterocyclic radical template of H17 (WO 02040480), H18, H19 and H20 (WO 9835967) type.In the variant of aforesaid method, crucial Ar
1Base can be according to circumstances at the synthetic latter stage, and the transition metal-catalyzed pair of aryl coupling process of having known through affiliated field introduced (flow process 15).Reported the N arylation of other transition metal mediation of bicyclic heterocycle, Tetrahedron Lett for example, 44; 2003; 3359-3362 is said, wherein in the presence of venus crystals (II), molecular sieve and alkali, under mild conditions, uses aryl boric acid to accomplish arylation, and said alkali is preferably phenanthroline.Except that said report, studied heterocycle functional group's the outer N-H arylation of other effective ring.The most normally used method is based on palladium, nickel or copper catalyst and aryl halide or aromatic yl sulphonate.
(Bioorganic Medicinal Chemistry Lett 12,2002 2133-2136) has described also [4,3-d] pyrimidine of 3-arylpyrazole, H51 type to document.In the backflow pyridine, handle the intermediate PyrazolopyrimidinonecGMP (75) (flow process 16) that N-alkyl pyrazole (74) produces moderate yield with sulfo-acetimidate hydrobromate.
Flow process 16
In addition, obtain to keep the similar target of said dicyclic ring through flow process 1 and flow process 20 described standard halogenations, nucleophilic substitution operation.In certain embodiments, can incorporate one of said heteroatoms into 6:5 ring tie point, said instance comprises heteronucleus H51-54, H61-63, H70-84 and the H110-113 in the table 6.
Flow process 17
Under the field 3-arylpyrazole of having known the H53 type also [1,5-a] pyrimidine and its can obtain from flow process 17 described aryl acetonitriles.Can be through the conversion of various described synthesis method effects to intermediate ketone nitrile (78,79,80).Can realize all intermediates are cyclized into amino-pyrazol through heating hydrazine HCl in the alcoholic solvent of for example ethanol or Virahol.Can in backflow diox or THF, use various 'beta '-ketoesters to construct the 26 yuan of ring and produce 82 type pyrazolos [1,5-a] pyrimidone, it is further processed through standard halogenation nucleophilic displacement operation.In alternate embodiment, can synthesize 3-arylpyrazole also [1,5-a] pyrimidine (Scheme 18) nuclear, wherein Ar through flow process 18 described synthesis flows
1Root bank (Negishi) or the coupling of Suzuki (Suzuki) type through crucial transition-metal catalyst mediation are introduced.What also can significantly mention at this moment is also can prepare 7-chloro-3-bromine pyrazolo [1,5-a] pyrimidine (87) (for example referring to J Med.Chem, 1976, the 19 volumes, No.4,512) through the direct bromination of N-bromo-succinimide by 7-chlorine condensed-bicyclic.
Flow process 18
Contain heteroatomic other preferred nuclear scaffold of the present invention (core scaffolds) at the link position that encircles and comprise the described pyrazolo of following flow process 18b [1,5-a] triazine and pyrazolo [1,2-a] pyrimidine.In addition, can similar organic chemistry method be used for 6 yuan of rings are fused to pyrazoles or pyrrole nucleus.The reaction that 4-aryl-3-amino-pyrazol and ethyl acetimidate produce the intermediate amidine is to make up pyrazolo [1; 5-a] committed step of triazine 91; Said intermediate and diethyl carbonate produce 65 triazones in the presence of sodium ethylate, its can be then through standard chlorination, nucleophilic displacement generating step Rup-3 selectivity of the present invention insulin secretion stimulators (referring to J Med Chem 2000,43; 3,449).Perhaps, can produce pyrazolo [making 2-a] pyrimidine (referring to WO/9835967) (flow process 18b) through in the backflow diox, reacting by three substituted azoles and methyl aceto acetate.
Flow process 18b
Can through the described method of flow process 19a obtain pyrazolo of the present invention [2,3-d] pyrimidine derivatives (J Med Chem, 1997,40,1749-1754).Can in the presence of the catalysis benzoyl peroxide, be easy to the propane dinitrile verivate bromination of deriving with the 1-13 Equivalent of NBS with Knoevenagel.With Ar
1NH
2Subsequent reactions produce amino-pyrroles intermediate (97).Cyclisation, then the cyclic action of hydrolysis nitrile and phosphoric acid mediation is the verified synthesis method that is used for synthetic pyrimidine ring.
Flow process 19a
Can adopt the for example synthetic approach of selectivity of the Heck mediation cyclic action of the described 5-alkynyl of flow process 19b-4-aniline pyrimidine.
Flow process 19b
Can use microwave to synthesize according to circumstances and promote to get into rapidly many The compounds of this invention (flow process 20).The Smith synthesizer of Personal Chemistry is a commercially available focusing position heating tool, and it provides the safety and the condition of homogeneous more for carrying out described base catalysis substitution reaction in the flow process.Said conversion (Q=NR wherein
4) alkali that adopted comprises tertiary amine, Xiu Nige (Hunig) alkali (meaning is di-isopropyl-ethamine), N-methylmorpholine of triethylamine for example etc.Perhaps, one of ordinary skill in the art can adopt alkalimetal hydride, alkaline carbonate (Li for example
2CO
3, Na
2CO
3, K
2CO
3Deng), alkali metal hydrocarbonate (LiHCO for example
3, NaHCO
3, KHCO
3Deng).Q=N wherein, can adopt inertia low-carbon alkyl alcoholic solvent (for example MeOH, EtOH,
1-PrOH, n-BuOH etc.) or Q=O wherein, for example THF, 1 can be used, the ether solvents of 4-diox etc.For the reaction times of for example reaching 104 and 105 representative instance can be the scope of about 300s to about 3000s, and (wherein Q O) is extremely about 48h of about 20min when adopting the convention by the use of thermal means.
Of flow process 21, use similar transition metal-catalyzed coupling to obtain the molecule of general formula 107-111 (flow process 21), the wherein " Ar of midbody 106
1" substituting group (halogen=Br, I) (is NR through modification to produce similar alkylamino substituting group
aR
b, R wherein
aAnd R
bAs described herein is H, C independently separately
1-6Alkyl or warp replace C
1-6Alkyl, or R
aAnd R
bForm heterocycle with nitrogen).Perhaps the CuI catalysis method is used for C-O forms that (document is referring to S L Buchwald, Organlc Lett, 2002 through Buchwald is described; 4,6,973-976); Use (for example) 10mol%CuI, 20mol% 1,10-phenanthroline, 2 equivalent Cs through under 110 ℃, lasting 18h
2CO
3(flow process 21d) carries out Ar in matrix
1Iodine replaces, and linker atom can be a Sauerstoffatom.From halogen midbody 106 other important organo-metallic being changed into active analogue thereof of the present invention comprises and well-knownly introduces aryl or heteroaryl [Ar through the suitable substituted aryl boric acid of " Suzuki coupled reaction " palladium catalysis coupling
4] (flow process 21e).
The Suzuki coupling representes to be widely used in the method for aryl-linking compound, and said method is large-scale application.Unfortunately, long-time interior this reaction is limited to aromatic bromide, aryl iodide or electron deficiency aryl muriate as raw material.Therefore, use the general method non-availability of the aryl muriate preparation aryl-linking compound of wanting cheap and that obtain easily.Yet in nearly 2 years, studied some and be used for the novel method of aryl muriate Suzuki coupling.Said method can effectively be synthesized dibenzyl, and is irrelevant with the replacement type and the electronic property of raw material.The Fu of study group, Buchwald, Guram, the theorem that Beller and Trudell and Nolan studied is given prominence in " the modern method of the crosslinked coupling of Suzuki ": the general synthesis method of said long-term expectation is used the aryl muriate.Groger，Harald，Journal?filer?Praktische?Chemie(Weinheim，Germany)(2000)，342(4)，334-339。Perhaps can use other metal catalytic conversion to introduce other functional group, for example under the microwave irradiation condition, use the cyanogenation of zinc cyanide (II) acquisition general formula 108 compounds or the Pd catalysis " Shao Na lid hila (Sonogashira) reaction " (flow process 21c) of existing abundant document record to introduce the alkynes end.Described recently the coupling of Shao Na lid hila use the appropriate reaction condition do not exist fully palladium catalyst under preparation almost the product of wanting of quantitative output (document referring to " First Examples of Transition-Metal Free Sonogashira-Type Couplings " Leadbeater, Nicholas E, Marco, Maria; Tominack, Bonnie J, Organic Letters (2003); 5 (21), 3919-3922, and transition-metal-free Sonogashira-type coupling reactions in water; Appukkuttan, Prasad, Dehaen; Wim, Van der Eycken, Enk; European Journal of Organic Chemistry (2003), (24), 4713-4716).
Flow process 21
One specific embodiment is for working as " Ar
1" on halogen when being positioned at the benzyl ring contraposition.In another specific embodiment of the present invention, halogen is three substituted pyridines part (midbody 113) 3 locational chlorine.Flow process 22 has been described the organic transformation metal catalytic method that replaces said halogen.
Specific wherein D=NCOORc, the wherein R of being substituted by of The compounds of this invention
cBe C
1-6Alkyl or C
3-7Naphthenic base and can further being substituted separately.The carbamate of this type can be directly by the intermediate preparation of flow process 20 and 21 described D=NH.In specific reactions, the suitable nitrogen-protecting group of use group (for example in the process of further chemical modification nuclear
tBoc, Cbz, Moz, Alloc, Fmoc etc.) be necessary.The standard reagent realization (it can be included in and be selected from methyl alcohol, ethanol, the trimethyl carbinol, THF, 1, the TFA in the alcohol of 4-diox etc. or the ether solvents system, mineral acid, palladium/hydrogen etc.) that can use one of ordinary skill in the art to be familiar with goes to reach protection.Target molecule contains in the situation of 2 protection bases, can adopt the orthogonally protect method.Therefore can follow modification removes to protect secondary amine (D=NH).
Flow process 22
Flow process 23 and the said chemical process of 24 and 25 explanations wherein can produce carbamate, urea or acid amides with appropriate reaction in the inert solvent system in the presence of alkali (for example can be the tertiary amine base such as TEA, DIEA etc.).
Of flow process 23, can be through in the inert solvent that has or do not have alkali, using R
cThe urea alkane reaction of OCO-halogenide (wherein R is as indicated above, and halogenide is chlorine, bromine or iodine, and what be particularly useful is chlorine) obtains urea alkane 116.Suitable alkali comprises alkaline carbonate (for example yellow soda ash, salt of wormwood etc.), alkali metal hydrocarbonate (for example sodium hydrogencarbonate, saleratus etc.), alkali metal hydroxide (for example sodium hydroxide, Pottasium Hydroxide etc.), tertiary amine (for example N, N-diisopropylethylamine, triethylamine, N-methylmorpholine etc.) or aromatic amine (for example pyridine, imidazoles, gather-(4-vinylpridine) etc.).Inert solvent comprises low-carbon (LC) halon solvent (for example methylene dichloride, ethylene dichloride, chloroform etc.), ether solvents (for example THF 、 diox etc.), aromatic solvent (for example benzene, toluene etc.) or polar solvent (for example N, dinethylformamide, DMSO 99.8MIN. etc.).Temperature of reaction is preferably about 0 ℃ to 100 ℃ in about-20 ℃ to 120 ℃ scope.
Flow process 23
Shown in flow process 24, acid goes to protect the amine midbody of 117 gained can functionalised to being expressed as the acid amides of material 118.4NHCl among carbamate 117 first Yu dioxs or the TFA is reacted in methylene dichloride, and then make itself and carboxylic acid (R with dehydrating condensation agent
dCO
2H, used like flow process 24; R
dBe Ar
2, or C
1-6-alkylidene group-Ar
2Ar
2/3Can be substituted or not be substituted and have a definition as herein described) further reaction produces acid amides 118 of the present invention in the inert solvent that has or do not have alkali.Said dehydrating condensation agent comprises dicyclohexyl carbodiimide (DCC), 1; 3-di-isopropyl carbodiimide) (DIC), 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride (EDCHCl), phosphofluoric acid bromo-three-tetramethyleneimine-Phosphonium (PyBroP), phosphofluoric acid benzotriazole base oxygen base three (dimethylaminos) ,-Phosphonium (BOP), phosphofluoric acid O-(7-pyridine and triazol-1-yl)-1; 1; 3,3-tetramethyl-urea (HATU) or 1-cyclohexyl-3-methylated polystyrene-carbodiimide.Alkali comprises tertiary amine (for example N, N-diisopropylethylamine, triethylamine etc.).Inert solvent comprises low-carbon (LC) halon solvent (for example methylene dichloride, ethylene dichloride, chloroform etc.), ether solvents (for example THF 、 diox etc.), nitrile solvent (for example acetonitrile etc.), amide solvent (N; Dinethylformamide, DMAC N,N etc.) and its mixture.According to circumstances, can I-hydroxybenzotriazole (HOBT), HOBT-6-formamido-methylated polystyrene or 1-hydroxyl-7-pyridine and triazole (HOAT) be used as reagent.Temperature of reaction is preferably about 0 ℃ to 40 ℃ in about-20 ℃ to 50 ℃ scope.
Perhaps, can be through in inert solvent, using sour halogenide (R for example
dCOCl) and alkali carry out acid amides reaction and obtain acid amides 118 of the present invention.Alkali comprises alkaline carbonate (for example yellow soda ash, salt of wormwood etc.), alkali metal hydrocarbonate (for example sodium hydrogencarbonate, saleratus etc.), alkali metal hydroxide (for example sodium hydroxide, Pottasium Hydroxide etc.), tertiary amine (for example N, N-diisopropylethylamine, triethylamine, N-methylmorpholine etc.) or aromatic amine (for example pyridine, imidazoles, gather-(4-vinylpridine) etc.).Inert solvent comprises low-carbon (LC) halon solvent (for example methylene dichloride, ethylene dichloride, chloroform etc.), ether solvents (for example THF 、 diox etc.), amide solvent (N for example; Dinethylformamide, DMAC N,N etc.), aromatic solvent (benzene, toluene, pyridine etc.) and its mixture.Temperature of reaction is preferably about 0 ℃ to 40 ℃ in about-20 ℃ to 50 ℃ scope.
Flow process 24 is also explained, can acid amides 11g and reductive agent be reacted generation amine 119 of the present invention in inert solvent.Reductive agent comprises composite alkali aluminum hydrogenate (for example lithium aluminum hydride etc.), alkali metal borohydride (for example lithium borohydride etc.), basic metal tri-alkoxy alanate (for example hydrogenation three-tert.-butoxy aluminium lithium etc.), dialkyl aluminum hydride (for example diisobutylaluminium hydride etc.), borine, Dialkylborane (for example diisoamyl borine etc.), basic metal trialkylboron hydrogenate (for example lithium triethyl-boron hydrogenate etc.).Inert solvent comprises ether solvents (for example THF 、 diox etc.), aromatic solvent (for example toluene etc.) and its mixture.Temperature of reaction is preferably about 50 ℃ to 120 ℃ in about-78 ℃ to 200 ℃ scope.
Perhaps, amine 119 of the present invention can through have or do not have acid inert solvent in sour de-protected secondary amine midbody and aldehyde (R
dCHO) and the reductive amination process of reductive agent obtain.Reductive agent comprises sodium triacetoxy borohydride, sodium cyanoborohydride, Peng Qinghuana, borine-pyridine complex etc.Inert solvent comprises low-carbon alkyl alcoholic solvent (for example methyl alcohol, ethanol etc.), low-carbon (LC) halon solvent (for example methylene dichloride, ethylene dichloride, chloroform etc.), ether solvents (for example THF, diox etc.), aromatic solvent (for example benzene, toluene etc.) and its mixture.Acid comprises mineral acid (for example spirit of salt, sulfuric acid etc.) or organic acid (for example acetate etc.).Temperature of reaction is about-20 ℃ to 120 ℃ a scope, is preferably about 0 ℃ to 100 ℃.In addition, this reaction can be carried out under microwave condition according to circumstances.
In another method, can with acid go to protect 117 intermediate amine product directly and alkylating agent in the presence of alkali in inert solvent alkylation amine 119 is provided, said alkylating agent for example is R
d-halogenide (R wherein
dFor being substituted or unsubstituted C
1-6Alkyl or be substituted or unsubstituted C
1-6Alkyl-Ar, and halogenide is chlorine, bromine and iodine).Said alkali comprises alkaline carbonate (for example yellow soda ash, salt of wormwood etc.), alkalimetal hydride (for example sodium hydride, potassium hydride KH etc.), alkali metal alcoholates (for example potassium tert.-butoxide, sodium tert-butoxide etc.), lithium alkylide (for example tert-butyl lithium, n-Butyl Lithium etc.).Inert solvent comprises ether solvents (for example THF 、 diox etc.), aromatic solvent (for example benzene, toluene etc.), amide solvent (for example N, dinethylformamide etc.) and its mixture.Temperature of reaction is preferably about 0 ℃ to 100 ℃ in about-20 ℃ to 120 ℃ scope.
The alkali existence that flow process 24 is also shown in the inert solvent prepares other compound of the present invention with alkyl-halogenide (wherein halogenide is chlorine, bromine and iodine) alkylation by the nitrogen in the urea of 118 expressions down.Alkali comprises alkalimetal hydride (for example sodium hydride, potassium hydride KH etc.), alkali metal alcoholates (for example tertiary butyl potassium alcoholate, tertiary butyl sodium alkoxide etc.), lithium alkylide (for example tert-butyl lithium, n-Butyl Lithium etc.).Inert solvent comprises ether solvents (for example THF 、 diox etc.), aromatic solvent (for example benzene, toluene etc.), amide solvent (for example N, dinethylformamide etc.) and its mixture.Temperature of reaction is preferably about 0 ℃ to 100 ℃ in about-20 ℃ to 120 ℃ scope.
Of flow process 25 in addition, can be by going to protect general midbody 120 and making amine (meaning is D=NH) and various isocyanic ester (R
aNCO, wherein R
aHave definition as herein described) reaction acquisition urea 121 in the inert solvent that has or do not have alkali.Suitable alkali comprises alkaline carbonate (for example yellow soda ash, salt of wormwood etc.), alkali metal hydrocarbonate (for example sodium hydrogencarbonate, saleratus etc.), alkali metal hydroxide (for example sodium hydroxide, Pottasium Hydroxide etc.), tertiary amine (for example N, N-diisopropylethylamine, triethylamine, N-methylmorpholine etc.) or aromatic amine (for example pyridine, imidazoles etc.).Inert solvent comprises low-carbon (LC) halon solvent (for example methylene dichloride, ethylene dichloride, chloroform etc.), ether solvents (for example THF 、 diox etc.), aromatic solvent (for example benzene, toluene etc.) or polar solvent (for example N, dinethylformamide, DMSO 99.8MIN. etc.).Temperature of reaction is preferably about 0 ℃ to 100 ℃ in about-20 ℃ to 120 ℃ scope.
Of flow process 25b in addition, can be by going to protect general midbody 120 and making amine (meaning is D=NH) and various isothiocyanic acid ester (R
aNCS, wherein R
aHave definition as herein described) reaction acquisition thiocarbamide 122 in the inert solvent that has or do not have alkali.Suitable alkali comprises alkaline carbonate (for example yellow soda ash, salt of wormwood etc.), alkali metal hydrocarbonate (for example sodium hydrogencarbonate, saleratus etc.), alkali metal hydroxide (for example sodium hydroxide, Pottasium Hydroxide etc.), tertiary amine (for example N, N-diisopropylethylamine, triethylamine, N-methylmorpholine etc.) or aromatic amine (for example pyridine, imidazoles etc.).Inert solvent comprises low-carbon (LC) halon solvent (for example methylene dichloride, ethylene dichloride, chloroform etc.), ether solvents (for example THF 、 diox etc.), aromatic solvent (for example benzene, toluene etc.) or polar solvent (for example N, dinethylformamide, DMSO 99.8MIN. etc.).Temperature of reaction is preferably about 0 ℃ to 100 ℃ in about-20 ℃ to 120 ℃ scope.
Flow process 26 explanation synthetic to alkyl sulfone (124) of the present invention, wherein R
10-R
13Have and identical definition described herein, wherein W is selected from the heterocycle of table 6 [H1-H116].The universal method for preparing said sulfone is included in strong acid catalyst and exists and use aryl sulfonyl halogenide or aryl sulfonic acid sulfide oxidation or sulfonylation aromatic hydrocarbon down (general document is referring to the Organic Chemistry of Sulfur; Oae S; Ed; Plenum Press New York, 1977).To the optimal conversion of aromatic hydrocarbon 124 to use 5mol% among the DMSO (CuOTf) while hot
2PhH and 10mol%N, N '-dimethyl-ethylenediamine reach through people's such as Wang method that (document is referring to Wang Z.; Baskin J M, Org Lett, 2002,4,25,4423-4425), wherein halogen is preferably iodine.In certain embodiments, R
10And R
13Independent separately is H, halogen or C
1-6Alkyl; R
11And R
12All be H, halogen=Br, I.
Flow process 27 describes 3, the synthesis method of 5-oxadiazole variant.With amidoxime 126 and 4-hydroxy piperidine, 128 usefulness zinc chloride (II) the catalysis couplings of CNBr deutero-, produce structural unit 129 after the s.t., then it is used for flow process 1 and 20 described reaction sequence.
Flow process 27
In preferred embodiment of the present invention, can with sulfoamido introduce Ar between the position or contraposition.This can be through the multistep synthetic operation that is amenable to; Comprise ammonia and SULPHURYL CHLORIDE reaction (flow process 28A) are reached; Perhaps can obtain sulphonamide through making sulphonate and for example hydroxylamine-o-sulfonic acid or two-(2,2,2-three chloroethyls)-azodicarboxylate's electrophilic nitrogenous source reaction.Preferred 3-methoxyl group-3-dislikes propane-1-sulfinic acid ester can be by independent alkanisation as sulfinic acid ester donor part and can then remove through β-elimination reaction.Gained-sulfinic acid ester and the reaction of electrophilic nitrogenous source produce the first sulphonamide analogue of the present invention.Said midbody can further be modified according to circumstances to be become for example by the acid amides shown in the general formula 132.The acyl group sulphonamide of said type can be through using sour halogenide or acid anhydride (R for example
gCOCl or (R
gCO)
2O) and alkali in inert solvent amidate action obtain (flow process 28C) alkali and comprise alkaline carbonate (for example yellow soda ash, salt of wormwood etc.), alkali metal hydrocarbonate (for example sodium hydrogencarbonate, saleratus etc.), alkali metal hydroxide (for example sodium hydroxide, Pottasium Hydroxide etc.), tertiary amine (for example N, N-diisopropylethylamine, triethylamine, N-methylmorpholine etc.) or aromatic amine (for example pyridine, imidazoles, gather-(4-vinylpridine) etc.).Inert solvent comprises low-carbon (LC) halon solvent (for example methylene dichloride, ethylene dichloride, chloroform etc.), ether solvents (for example THF 、 diox etc.), amide solvent (N for example; Dinethylformamide, DMAC N,N etc.), aromatic solvent (benzene, toluene, pyridine etc.) and its mixture.Temperature of reaction is preferably about 0 ℃ to 40 ℃ in about-20 ℃ to 50 ℃ scope.
Flow process 28
The blocking group that during more synthetic The compounds of this invention, possibly need various functional groups.Therefore, be suitable for the extensively synthetic representative blocking group of changing and be disclosed in Greene and Wuts, Protective Groups in Organic Synthesis; The 3rd edition, John Wiley & Sons, New York; 1999, its disclosure is incorporated herein by reference fully.
The present invention also comprises diastereomer and optical isomer, for example comprises the mixture of the enantiomer of racemic mixture and indivedual enantiomer and diastereomer, and this is the result of specific formula (I) compound structure asymmetry.The whole bag of tricks of knowing through field practitioner under using can realize that the selectivity of separation or individual isomers of individual isomers is synthetic.Compound disclosed herein can asymmetric (for example having one or more stereocenters).Except as otherwise noted, otherwise be meant the for example steric isomer of enantiomer and diastereomer.The The compounds of this invention that contains asymmetric alternate c atoms can separate through optical activity or racemic form.How the method by optical activity feedstock production optical activity form is known in affiliated field, for example resolves racemic mixture through optics or through the stereoselectivity synthesis method.Many geometrical isomers of the two keys of paraffin, C=N, two substituted cycloalkyls (promptly 1,4-cyclohexyl) etc. also are present in the compound as herein described, and the present invention expects all said desmotropes.Described the cis-isomeride and the trans-isomer(ide) of The compounds of this invention, and they can be used as isomer mixture or separate as independent isomeric forms.
Indication that prevents and/or treats and method
The aforementioned useful purposes of the The compounds of this invention that discloses except that this paper, The compounds of this invention can be used for prevention or treats other disease.These diseases comprise following instance without limitation.
The cell that the insulin signaling that the most significant pathology of type ii diabetes is the target tissue place weakens the generation Regular Insulin of (" insulin resistance ") and pancreas can not respond the Regular Insulin that the hyperglycemia signal secretes suitable degree.At present the treatment latter's therapy comprises β cell ATP sensitive potassium-channel suppressor factor being used to the exciting endogenous insulin deposit to discharge, or the exogenous insulin that comes into operation.The two can not be realized all that accurate normalizing of glucose level and both bring and bring out hypoglycemic danger.Owing to these reasons, research and development acting medicine in the glucose dependent behavior, promptly the glucose signals synergistic agent causes people's strong interest.The physiology transmission system that plays a role has by this way overcharged branch and has characterized and comprise enteron aisle peptide GLP-1 1, GIP and PACAP.These hormones work in the stimulating pancreas β cell via its homology G-protein-coupled receptor and produce cAMP.The cAMP that is increased appears not cause during empty stomach or stage before the meal, to stimulate Regular Insulin to discharge.Yet; The biochemical target of a series of cAMP signals comprises that the warp of ATP-sensitive potassium-channel, voltage sensitivity potassium-channel and exocytosis mechanism (exocytotic machinery) is modified so that the insulin secretion that stimulates in response to GLPP obviously strengthens.In view of the above, therefore the release that the novel agonist β cell GPCR (comprising RUP3) with similar functions also maybe stimulation of endogenous Regular Insulin also promote that the blood sugar amount is normal in the type ii diabetes.
Confirm that also (for example) can promote Beta cell proliferation, suppresses the β necrocytosis and therefore improve island agglomerate (islet mass) because of GIP1 stimulates the cAMP that is increased.The positive effect that we are expected on the β cell mass is all useful to the type i diabetes that Regular Insulin produces insufficient type ii diabetes and improper autoimmunity response destruction β cell.
Some comprise that the β cell GPCR of RUP3 also is present in the hypothalamus, and wherein they are regulated hunger sensation, satiety, minimizing ingestion of food, control or reduce body weight and energy expenditure.Therefore, in view of the function of said β cell GPCR in the hypothalamus circuit, thereby the agonist of these acceptors or inverse agonist can alleviate hunger sensation, promote satiety adjusting body weight.
Confirm fully that also metabolic disease applies negative impact to other physiological system.Therefore, there is multiple symptom that (the for example cardiovascular diseases in type i diabetes, type ii diabetes, improper glucose tolerance, insulin resistance, hyperglycemia, hyperlipidaemia, hypertriglyceridemia, hypercholesterolemia, hyperlipemia, obesity or " the X syndromes ") takes place jointly usually or obviously is secondary to the secondary disease (for example ephrosis, peripheral neurophaty) of mellitus.Therefore we expect that effective treatment diabetic symptom will be of value to and connect the venereal disease shape in said.
In some embodiments of the invention, said metabolic-related disorders is hyperlipidaemia, type 1 diabetes, diabetes B, specially send out that vascular restenosis after property type 1 diabetes (1b type), the invisible autoimmune diabetes (LADA) of being grown up, early onset diabetes B (EOD), youth's property atypia mellitus (YOAD), young adult morbidity type mellitus (MODY), malnutritive dependency mellitus, gestational diabetes, coronary heart disease, ishemic stroke, the vascular surgery, peripheral vascular disease, intermittent claudication, myocardial infarction (for example necrosis and apoptosis), hyperlipemia, post-prandial lipemia, sugar tolerance impaired (IGT) symptom, the impaired symptom of fasting blood sugar, metabolic acidosis, ketosis, sacroiliitis, obesity, osteoporosis, hypertension, congestive heart failure, left ventricular hypertrophy, peripheral arterial disease, diabetic retinopathy, degeneration of macula, cataract, diabetic nephropathy, glomerulosclerosis, chronic renal failure, diabetic neuropathy, metabolic syndrome, X syndromes, premenstrual syndrome, coronary heart disease, stenocardia, thrombosis, atherosclerosis, myocardial infarction, TCI, apoplexy, vascular restenosis, hyperglycemia, hyperinsulinemia, hyperlipidaemia, hypertriglyceridemia, insulin resistance, glucose metabolism are bad, the impaired symptom of sugar tolerance, the impaired symptom of fasting blood sugar, obesity, erective dysfunction, skin and reticular tissue illness, pedopathy and ulcerative colitis, endothelial function is unusual and the blood vessel compliance is impaired.
One aspect of the present invention is about treating the method for individual metabolic-related disorders, and it comprises to the individuality of the said treatment of needs throws and The compounds of this invention or its medical composition of treating effective dose.In certain embodiments, said metabolic-related disorders is type i diabetes, type ii diabetes, improper glucose tolerance, insulin resistance, hyperglycemia, hyperlipidaemia, hypertriglyceridemia, hypercholesterolemia, hyperlipemia or X syndromes.In certain embodiments, said metabolic-related disorders is a type ii diabetes.In certain embodiments, said metabolic-related disorders is a hyperglycemia.In certain embodiments, said metabolic-related disorders is a hyperlipidaemia.In certain embodiments, said metabolic-related disorders is a hypertriglyceridemia.In certain embodiments, said metabolic-related disorders is a type i diabetes.In certain embodiments, said metabolic-related disorders is a hyperlipemia.In certain embodiments, said metabolic-related disorders is the X syndromes.Said in certain embodiments individuality is a Mammals.Said in certain embodiments Mammals is human.
One aspect of the present invention is about reducing the method for individual ingestion of food, and it comprises the individuality throwing and The compounds of this invention or its medical composition of treating effective dose that reduces said ingestion of food to needs.Said in certain embodiments individuality is a Mammals.Said in certain embodiments Mammals is human.
One aspect of the present invention is about bringing out the method for individual satiety, and it comprises to its individuality of needs throws The compounds of this invention or its medical composition with the treatment effective dose.Said in certain embodiments individuality is a Mammals.Said in certain embodiments Mammals is human.
One aspect of the present invention is about the method for control or the increase of minimizing whose body weight, and it comprises to individual The compounds of this invention or its medical composition of throwing and treating effective dose of the said treatment of needs.Said in certain embodiments individuality is a Mammals.Said in certain embodiments Mammals is human.
Some embodiments of the invention are about 185 to about 45 method about human weight index wherein.In certain embodiments, human weight index is about 25 to about 45.In certain embodiments, human weight index is about 30 to about 45.In certain embodiments, human weight index is about 35 to 45.
One aspect of the present invention is about regulating the method for individual RUP3 acceptor, and it comprises makes said acceptor contact with The compounds of this invention or its medical composition.In certain embodiments, said compound is an agonist.In certain embodiments, said compound is an inverse agonist.In certain embodiments, said compound is an antagonist.In certain embodiments, the adjusting to the RUP3 acceptor is treatment metabolic-related disorders and its complication.In certain embodiments, said metabolic-related disorders is type i diabetes, type ii diabetes, improper glucose tolerance, insulin resistance, hyperglycemia, hyperlipidaemia, hypertriglyceridemia, hypercholesterolemia, hyperlipemia or X syndromes.In certain embodiments, said metabolic-related disorders is a type ii diabetes.In certain embodiments, said metabolic-related disorders is a hyperglycemia.In certain embodiments, said metabolic-related disorders is a hyperlipidaemia.In certain embodiments, said metabolic-related disorders is a hypertriglyceridemia.In certain embodiments, said metabolic-related disorders is a type i diabetes.In certain embodiments, said metabolic-related disorders is a hyperlipemia.In certain embodiments, said metabolic-related disorders is the X syndromes.Said in certain embodiments individuality is a Mammals.Said in certain embodiments Mammals is human.
Some embodiments of the invention comprise a kind of method of regulating individual RUP3 acceptor, and it comprises makes said acceptor contact with The compounds of this invention, and wherein the adjusting to the RUP3 acceptor is to reduce individual ingestion of food.Said in certain embodiments individuality is a Mammals.Said in certain embodiments Mammals is human.In certain embodiments, said human weight index is about 185 to about 45.In certain embodiments, said human weight index is about 25 to about 45.In certain embodiments, said human weight index is about 30 to about 45.In certain embodiments, said human weight index is about 35 to about 45.
Some embodiments of the invention comprise a kind of method of regulating individual RUP3 acceptor, and it comprises makes said acceptor contact with The compounds of this invention, and wherein the adjusting to the RUP3 acceptor is to bring out individual satiety.Said in certain embodiments individuality is a Mammals.Said in certain embodiments Mammals is human.In certain embodiments, said human weight index is about 185 to about 45.In certain embodiments, said human weight index is about 25 to about 45.In certain embodiments, said human weight index is about 30 to about 45.In certain embodiments, said human weight index is about 35 to about 45.
Some embodiments of the invention comprise a kind of method of regulating individual RUP3 acceptor, and it comprises makes said acceptor contact with The compounds of this invention, and wherein the adjusting to the RUP3 acceptor is control or reduces the whose body weight increase.Said in certain embodiments individuality is a Mammals.Said in certain embodiments Mammals is human.In certain embodiments, said human weight index is about 18 5 to about 45.In certain embodiments, said human weight index is about 25 to about 45.In certain embodiments, said human weight index is about 30 to about 45.In certain embodiments, said human weight index is about 35 to about 45.
One aspect of the present invention is used to treat the purposes of the medicine of metabolic-related disorders about compound manufacturing as herein described.In certain embodiments, said metabolic-related disorders is type ii diabetes, improper glucose tolerance, insulin resistance, hyperglycemia, hyperlipidaemia, hypertriglyceridemia, hypercholesterolemia, hyperlipemia or X syndromes.
One aspect of the present invention is used to reduce the purposes of the medicine of individual ingestion of food about compound manufacturing described herein.Said in certain embodiments individuality is a Mammals.Said in certain embodiments Mammals is human.In certain embodiments, said human weight index is about 185 to about 45.In certain embodiments, said human weight index is about 25 to about 45.In certain embodiments, said human weight index is about 30 to about 45.In certain embodiments, said human weight index is about 35 to about 45.
One aspect of the present invention is used to reduce the purposes of the medicine of individual satiety about compound manufacturing described herein.Said in certain embodiments individuality is a Mammals.Said in certain embodiments Mammals is human.In certain embodiments, said human weight index is about 185 to about 45.In certain embodiments, said human weight index is about 25 to about 45.In certain embodiments, said human weight index is about 30 to about 45.In certain embodiments, said human weight index is about 35 to about 45.
One aspect of the present invention is used to control or reduce the purposes of the medicine of whose body weight increase about compound manufacturing described herein.Said in certain embodiments individuality is a Mammals.Said in certain embodiments Mammals is human.In certain embodiments, said human weight index is about 185 to about 45.In certain embodiments, said human weight index is about 25 to about 45.In certain embodiments, said human weight index is about 30 to about 45.In certain embodiments, said human weight index is about 35 to about 45.
One aspect of the present invention is about being used for the compound described herein through therapy for treating human body or animal body.
One aspect of the present invention is about being used for the compound described herein through therapy for treating human body or animal body metabolic-related disorders.
One aspect of the present invention is about being used for reducing through therapy the compound described herein of human body or animal body ingestion of food.
One aspect of the present invention is about being used for bringing out through therapy the compound described herein of human body or animal body satiety.
One aspect of the present invention is about being used for the compound described herein through therapy control or minimizing human body or animal body weight increase.
Medical composition
Another aspect of the present invention is about medical composition, and it wraps one or more The compounds of this invention, and one or more pharmaceutically acceptable supporting agents.Some embodiments of the invention are about medical composition, and it comprises The compounds of this invention and pharmaceutically acceptable supporting agent.
Some embodiments of the present invention comprise a kind of method for preparing medical composition, and it comprises at least a compound that makes any compound embodiment that discloses according to this paper and pharmaceutically acceptable supporting agent fusion.
Can prepare composite through any appropriate method, through both uniform mixing prepare with active compound and liquid or finely divided solid carriers or with it,, then then want mixture processed the shape of wanting usually if need.
Can conventional excipients be used for lozenge and capsule is used for oral administration medicine supplying, for example tackiness agent, weighting agent, acceptable wetting agent, compressing tablet lubricant and disintegrating agent.The liquid preparation that is used for oral administration medicine supplying can be solution, emulsion, water-based or oily suspension-s and syrupy form.Perhaps, oral prepns can be used water or other suitable liquid mediator regenerated dry powder form before use.Can in liquid preparation, add other additive, for example suspension agent or emulsifying agent, non-aqueous mediator (comprising edible oil), sanitas and seasonings and tinting material.Can through The compounds of this invention is dissolved in the suitable liquid mediator and with the solution filter sterilization fill then and seal prepare in suitable phial or the ampoule non-through the intestines formulation.This only is some instances that affiliated field is used for preparing many appropriate method of formulation.
Can The compounds of this invention be deployed into medical composition with the known technology in affiliated field.The known suitable pharmaceutically acceptable supporting agent except that those preceding text are mentioned in affiliated field; For example referring to Remington, The Science and Practice of Pharmacy, 20th Edition, 2000, Lippincott Williams & Wilkins, (editor: Gennaro, A R waits the people).
Though compound of the present invention is used for prevention or treatment the time might alternately come into operation with thick chemical or pure chemistry article form, is preferably said compound or active ingredient are provided with pharmaceutical formulation or the composition forms that further comprises pharmaceutically acceptable supporting agent.
Therefore progress of the present invention provides pharmaceutical formulation, and it comprises compound of the present invention or its pharmaceutically acceptable salt or verivate together with one or more pharmaceutically acceptable supporting agents and/or prevention composition.Said supporting agent must be " acceptable " and its receptor do not had excessive toxicity on the meaning compatible with other composition of said composite.
Pharmaceutical formulation comprise those be suitable for oral, rectum, nose, part (comprising oral cavity and hypogloeeis), vagina or non-through intestines (comprising intramuscular, subcutaneous and intravenously) types of administration or be suitable for through sucking, be blown into or the form of patch (transdermal patch) dispensing.Patch is through providing with the effective means absorption and the minimized medicine of drug degradation is distributed medicine with controllable rate.Usually, patch comprises impermeable bed course, separately pressure sensitive adhesive and the removable resist with release liner.One skilled in the art will understand and understand the technology that is suitable for making the effective patch of wanting according to skilled worker's needs.
Therefore compound of the present invention can be made into the form of pharmaceutical formulation and its unitary dose together with convention assistant agent, supporting agent or thinner, and said form can solid form adopt, for example lozenge or filled capsules; Or adopt with liquid form, for example solution, suspension-s, emulsion, elixir, gel or be filled with the capsule of same substance, all forms are used for oral; Be used for rectal administration with suppository form; Or be used for non-ly using through intestines (comprising subcutaneous) with the aseptic injectable solution form.Said medical composition and its unit dosage can comprise the convention composition of convention ratio; Have or do not have extra active compound or key element, and said unit dosage can contain with the active ingredient of the suitable any suitable effective dose of expectation dosage range every day that will adopt.
The medical composition that is used for oral administration medicine supplying can for example be the form of lozenge, capsule, suspension-s or liquid.Said medical composition is preferably processed the dose unit that contains the specified quantitative active ingredient.The instance of said dose unit is capsule, lozenge, powder, granule or suspension-s, together with following material: the convention additive of lactose, N.F,USP MANNITOL, W-Gum or yam starch for example; The tackiness agent of crystalline cellulose, derivatived cellulose, gum arabic, W-Gum or gelatin for example; The disintegrating agent of W-Gum, yam starch or Xylo-Mucine for example; And the lubricant of talcum or Magnesium Stearate for example.Said active ingredient also can composition forms injection come into operation, for example wherein can use salt solution, Vadex or water as suitable pharmaceutically acceptable supporting agent.
The compounds of this invention or solvolyte or its physiological function derivative can be used as medical composition, especially can be used as the active ingredient of RUP3 receptor modulators.Term " active ingredient " is defined in " medical composition " scope and should means the component of the medical composition that main pharmacological is provided, and on the contrary, will think that generally " nonactive composition " do not provide the medicine benefit.
The using dosage of The compounds of this invention can in wide region, change and such as routine and doctor knowledge, it should be adjusted according to indivedual symptoms of each individual instances.Said dosage depends on that (for example) waits to treat the character of disease and a disease that severity, patient's symptom, the compound that is adopted or institute treat or prevent is acute or chronic, or other active compound that except that The compounds of this invention, whether comes into operation.Representative dosage of the present invention includes, but is not limited to: about 0 001mg is to about 5000mg, about 0 001 to about 2500mg, about 0.001 to about 1000mg, 0 001 to about 500mg, 0 001mg about 250mg, about 0 001mg to 100mg, about 0 001mg about 50mg and about 0.001mg about 25mg extremely extremely extremely.The multidose that can come into operation in the middle of one day is especially thought when needing relative high amount of drug, for example 2,3 or 4 dosage.Look personal habits and fixed and, be necessary to increase or reduce dosage described herein if patient's doctor or monitoring person think fit.
Treat required active ingredient or its active salt or verivate amount not only along with selected specific salts but also along with character and the patient's age and the symptom variation of the approach of coming into operation, the symptom of treating, make a round of visits doctor or clinician will make final judgement.Generally speaking, how one of ordinary skill in the art understand from the model system that is generally animal model gained and in vivo release other model (for example human) outside the data.Usually animal model include, but is not limited to hereinafter instance 5 described rodent diabetes models (and for example Reed and Scribner at Diabetes; Obesity and Metabolism; 1,1999, known other animal model in the affiliated field of reporting among the 75-86).In the certain situation, these extrapolations are only based on the body weight of each animal model compared to another animal model (for example Mammals, preferred human), yet these extrapolations more commonly are not simply based on body weight and combined multiple factor.Representative factor includes, but is not limited to: patient's type, age, body weight, sex, diet and medical conditions; The severity of disease; Dosing way, pharmacology Consideration, the for example activity of the specific compound that adopts, effect, pharmacokinetics and toxicology overview; Whether utilized drug delivery, the disease of treating or preventing is acute or chronic or other active compound and as the part of drug regimen of except that formula (I) compound, whether also coming into operation.Multiple factor according to preceding text are enumerated is selected the dosage instructions about how to take medicine with compound of the present invention and/or composition therapeuticing disease symptom.Therefore the actual dose instructions about how to take medicine that adopted can change big and therefore can depart from the preferred dose instructions about how to take medicine, and one of ordinary skill in the art will be appreciated that dosage and dosage instructions about how to take medicine outside these typical ranges can be used in the method for the present invention through test and when suitable.
The dosage of wanting can come into operation under proper spacing with single dose or separate dose easily, for example every day two, three, four or more divided dose come into operation.Said divided dose can further be divided into for example many discrete loose interval dispensings again.Especially think suitable and come into operation when heavy dose of relatively, can with every day the dose precedent like 2,3 or 4 parts several portions dispensing.If suitably, look personal habits and dosage every day shown in being necessary surely to increase or reduce.
Compound of the present invention can be extensively different orally or non-come into operation through the intestines formulation.The pharmaceutically acceptable salt that can comprise compound of the present invention or The compounds of this invention to the obvious following dosage forms of one of ordinary skill in the art is as active constituent.
For from compound medical composition of the present invention, pharmaceutically acceptable suitable supporting agent may be selected to be solid, liquid or both mixtures.Solid formulation comprises powder, lozenge, pill, capsule, cartridge bag, suppository and particle dispersion.Solid carriers can be one or more materials, and they also can serve as thinner, seasonings, solubilizing agent, lubricant, suspension agent, tackiness agent, sanitas, lozenge disintegrating agent or cover material.
In powder, supporting agent is and the finely divided solid of finely divided active constituent blended.
In lozenge, active constituent is mixed with suitable proportion with the supporting agent with necessary adhesive capacity and is compressed into the shape and size that work is wanted.
Said powder and lozenge can contain the active compound of different weight percentage.Typical amount in powder or the lozenge can contain 05% to about 90% active compound; Yet the technician is necessary for the amount beyond this scope with understanding.The suitable supporting agent of powder and lozenge is magnesiumcarbonate, Magnesium Stearate, talcum, sucrose, lactose, pectin, dextrin, starch, gelatin, tragacanth gum, methylcellulose gum, Xylo-Mucine, low melt wax, cocoa wet goods.Terms " formulation " is intended to comprise the composite of active compound and cover material formation; Wherein said cover material is as providing capsular supporting agent, and therefore the active constituent that has or do not have supporting agent in the said capsule is surrounded by supporting agent that said supporting agent combines with active constituent.Similarly, comprise cartridge bag and suck agent.Lozenge, powder, capsule, pill, cartridge bag and lozenge can be used as the solid form that is suitable for oral administration medicine supplying.
As far as preparation suppository, at first will be for example glycerin fatty acid ester class foreign body low melt wax or theobroma oil fusion and said active constituent is dispersed in wherein.Then said fusion homogenizing mixture is poured into and had in the mould that makes things convenient for size, make its cooling and solidify.
The composite that is suitable for vaginal dosing can vaginal suppository, the form of tampon, emulsion, gel, paste, foams or spraying provides the known suitable supporting agent in field under they also have except that containing active ingredient.
Liquid formulation comprises solution, suspension-s and emulsion, for example water or water-propylene glycol solution.For example, can be deployed into the solution in the polyoxyethylene glycol aqueous solution through the enteral administration liquid formulation with non-.Can use suitable dispersant or moistening agent and suspension agent to allocate injection formulations according to known technology, for example aseptic injection water-based suspension-s or oily suspensions.Aseptic injection preparation also can be nontoxic non-thinner or aseptic injectable solution in the solvent or suspension-s of allowing through intestines, for example is dissolved in the solution in the 1,3 butylene glycol.Can accept adoptable in mediator and the solvent is water, woods Ge Shi (Ringer) solution and isotonic sodium chlorrde solution.In addition, convention adopts aseptic expressed oil as solvent or suspension medium.For this purpose, can adopt any gentle expressed oil, comprise synthetic property monoglyceride or triglyceride.In addition, for example oleic fatty acid can be used for preparing injection.
The compounds of this invention therefore can be deployed into be used for non-through intestines dispensing (for example through injection, like bolus injection or continuous infusion) and can unit dosage be present in the ampoule that added sanitas, in advance the filling injection pipe, on a small quantity inculcate or multi-dose container in.Said medical composition can for example be taked suspension-s, solution or the emulsion form in oiliness or the aqueous vehicles, and can contain the for example blender of suspension agent, stablizer and/or dispersion agent (formulatory agent).Perhaps, said active ingredient can be for by aseptic separation of sterile solid or the powder type that obtained from the solution freeze-drying, for constituting with the suitable mediator of for example aseptic apirogen water before use.
The aqueous solution that is suitable for orally using can prepare through active constituent being dissolved in the water and adding suitable tinting material, spices, stablizer and thickening material on demand.
The waterborne suspension that is suitable for orally using can be through preparing in the water that finely divided active constituent is scattered in have cohesive material, and said material is for example known the suspension agent class for natural or synthetical glue class, resene, methylcellulose gum, Xylo-Mucine or other.
Be also included within the solid formulation that changes into the liquid formulation that is used for oral administration medicine supplying before being about to use.Said liquid form comprises solution, suspension-s and emulsion.Said preparation also can contain tinting material, spices, stablizer, buffer reagent, artificial and natural sweeteners, dispersion agent, thickening material, solubilizing agent etc. except that active constituent.
To epidermis, can formulated of the present invention be become ointment, emulsion or lotion as far as topical administration, or be deployed into patch.
For example, can be with water-based or oleaginous base allotment ointment and emulsion when adding suitable thickening material and/or jelling agent.Can use or oleaginous base allotment lotion, and also contain one or more emulsifying agents, stablizer, dispersion agent, suspension agent, thickening material or tinting material as the lotion.
Be suitable for that the composite of topical administration comprises in mouth: lozenge, it comprises active ingredient in the flavoured base that is generally sucrose and gum arabic or tragacanth gum; Lozenge, it comprises active constituent in the inert base of for example gelatin and glycerine or sucrose and gum arabic; And mouth-washes, it is suitably comprising active ingredient in the liquid carrier.
Can for example use dropper, suction pipe or spray thrower (spray) by conventional approaches directly to nasal administration solution or suspension-s.Said composite can single agent or the multi-agent form provide.Under the latter instance of using dropper or suction pipe, can realize through the solution or the suspension-s of the suitable predetermined amount that comes into operation to the patient.Under the situation of spray thrower, can for example utilize metering atomizing spray pump to realize.
Realize that to respiratory tract dispensing aerosol composite also capable of using wherein said active ingredient is by providing in the pressurized package with suitable propelling agent.If with aerosol form (for example with the nasal aerosol form or through the sucking) formula that comes into operation (I) compound or comprise their medical composition, can for example use spray thrower, atomizer (nebulizer), pump spray, metered-dose inhaler or Diskus to offer medicine so.Can prepare through well-known to one skilled in the art method with the come into operation medical form of formula (I) compound of aerosol form.For example; Can adopt solution or the dispersion liquid of formula (I) compound in water, water/alcohol mixture or suitable salt brine solution with regard to its preparation; Use conventional additives (for example being benzylalcohol) or other suitable sanitas, the absorption enhancer that is used to increase bioavailability, solubilizing agent, dispersion agent and other therein, and (if suitably) can use for example comprise carbonic acid gas, like the conventional propellant of the CFC of Refrigerant 12, trichlorofluoromethane or dichloro tetrafluoro ethane etc.Said aerosol also can contain tensio-active agent expediently, like Yelkin TTS.Can use proportional valve to control drug dose.
Desire is in the composite (comprising composite in the nose) that respiratory tract comes into operation, and said compound generally should have for example about 10 microns or littler small particle size.Can for example obtain said particle diameter by affiliated field is known for micronized mode.When needs, can adopt the composite that is suitable for continuing to discharge active ingredient.
Perhaps said active ingredient can provide by dry powder form; The powdered mixture form that in suitable powder matrix, forms of compound for example, said powder matrix for example is the starch derivative of lactose, starch, for example Vltra tears and Vinylpyrrolidone polymer (PVP).Said powder supporting agent will form gel easily at nasal cavity.Said powder composition can unit dosage exists, for example with (as) capsule or the medicinal cupping or the film packaging form of gelatin, from the said powder that comes into operation of sucker capable of using wherein.
Said pharmaceutical preparation is preferably unit dosage.In the said form, said preparation is further divided into the unitary dose that contains the appropriate amount active constituent.Said unit dosage can be packaged preparation, and said packing contains the preparation of dispersion amount, for example packs the powder in lozenge, capsule and phial or the ampoule.Equally, said unit dosage can be capsule, lozenge, cartridge bag or a lozenge self, and perhaps it can be any said formulation of the proper number of packaged form.
The lozenge or the capsule that are used for oral administration medicine supplying are preferred compositions with the liquid that is used for the intravenously dispensing.
The compounds of this invention can exist with pharmaceutically acceptable salt form according to circumstances, comprises the pharmaceutically acceptable acid salt of being processed by pharmaceutically acceptable non-toxicity acid (comprising mineral acid and organic acid).Representative acid includes, but is not limited to acetate, Phenylsulfonic acid, benzyl acid, camphorsulfonic acid, Hydrocerol A, ethyl sulfonic acid, dichloro acetic acid, formic acid, FUMARIC ACID TECH GRADE, glucono-, L-glutamic acid, urobenzoic acid, Hydrogen bromide, spirit of salt, isethionic acid, lactic acid, maleic acid, oxysuccinic acid, racemic melic acid, methylsulfonic acid; Half glucaric acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phosphoric acid, Succinic Acid, sulfuric acid, tartrate, oxalic acid, tosic acid etc.; Journal of Pharmaceutical Science for example; 66; 2 (1977) listed pharmaceutically acceptable salt, it all is incorporated herein by reference.
Acid salt can the synthetic direct product form of compound obtain.Perhaps, free alkali can be dissolved in the suitable solvent that contains suitable acid, and said salt is through evaporating solvent or with salt or in addition with salt and separated from solvent acquisition.Can use the known method of skilled manpower to make The compounds of this invention and standard low molecular weight solvent form solvolyte.
Can The compounds of this invention be changed into " prodrug ".Term " prodrug " is meant by the group modified compound of the known particular chemical in affiliated field, and the bio-transformation of said group experience produces parent compound when coming into operation in individuality.Therefore can regard prodrug as contain one or more special-purpose nontoxicity blocking groups The compounds of this invention, said nontoxic blocking group is used for changing or eliminating with the transition mode characteristic of compound.With regard to general aspect, " prodrug " method is used to promote oral absorption.T.Higuchi and V.Stella; " Pro-drugs as Novel Delivery Systems, " A.C S Symposium Series the 14th volume and Bioreversible Carriers in Drug Design; Edward B.Roche compiles; American Pharmaceutical Association and Pergamon Press, 1987 provide discussion completely, and they all are incorporated herein by reference.
Some embodiments of the present invention comprise that a kind of preparation is used for the method for the medical composition of " combination treatment ", and it comprises at least a compound and at least a known pharmaceutical reagent as herein described and the pharmaceutically acceptable supporting agent fusion that makes any compound embodiment that discloses according to this paper.
Said in certain embodiments pharmaceutical reagent is selected from the group that is made up of following material: apolipoproteins-B secretory product/microsome tri-glyceride transfer protein (apo-B/MTP) suppressor factor, MCR-4 agonist, cholecystokinin-A (CCK-A) agonist, thrombotonin and norepinephrine reuptake inhibithors (for example sibutramine (sibutramine)), type sympathetic nerve agent, β
3Adrenoceptor agonists, Dopamine HCL (dopamine) agonist (for example bromocriptine (bromocriptine)), melanotropin receptor analogs, cannaboid 1 receptor antagonist [SR141716:N-(piperidines-1-yl)-5-(4-chloro-phenyl-)-1-(2 for example; The 4-dichlorophenyl)-4-methyl isophthalic acid H-pyrazole-3-carboxamide], melanochrome concentrating hormone antagonists, leptin (OB albumen), leptin analogue, leptin receptor agonist, galanin (galanin) antagonist, lipase inhibitor (for example orlistat (tetrahydrolipstatin, meaning is Orlistat)), appetite-inhibiting agent (for example Magainin (bombesin) agonist), neuropeptide-Y antagonist, Protirelin agent, trans-dehydroandrosterone or its analogue, glucocorticoid receptor agonist or antagonist, increase the food factor (orexin) receptor antagonist, the conjugated protein antagonist of urotensin (urocortin), glucagon-like peptide-1 receptor stimulant, CNTF (Axokine for example
TM), human cavy GAP-associated protein GAP (agouti-relatedproteins) (AGRP), Ge Ruilin (ghrelin) receptor antagonist, histamine 3 receptor antagonists or inverse agonist, neuromedin U receptor stimulant, the appetite-inhibiting agent (for example PHENTERMINE, SaH-42548 (mazindol) etc.) that produces sympathin, anoretic (for example Wellbutrin) etc.In another embodiment, said medicament is selected from the group that is made up of orlistat, sibutramine, bromocriptine, racephedrine, leptin and pseudoephedrine.
In certain embodiments; Said pharmaceutical reagent is selected from the group that is made up of following material: (for example shellfish special type (fibrates) comprises fenofibrate (fenofibrate), bezafibrate (bezafibrate), gemfibrozil (gemfibrozil), clofibrate (clofibrate) etc. to the medicine of sulfonylurea, meglitinide (meglitinides), biguanides, alpha-glucosidase inhibitor, peroxisome proliferation-activated receptors-γ (meaning is PPAR-γ) agonist, Regular Insulin, insulin analog, HMG-CoA reductase inhibitor, reducing cholesterol; Bile acid chelating agent comprises QUESTRAN (cholestyramine), cholestipol (colestipol) etc.; And nicotinic acid), anti-platelet agents (for example Frosst) (aspirin) and ADP receptor antagonist comprise (clopidogrel) more than the Crow, ticlopidine (ticlopidine) etc.), angiotensin converting enzyme inhibitor, angiotensin ii receptor antagonist and adiponectin (adiponectin).
Should notice that when RUP3 receptor modulators during it is not expected and only be used for the mankind, but is used for other non-human mammal yet as the active ingredient of medical composition.In fact; In animal health monitoring trustship recent progress; Considered the for example active agent of RUP3 receptor modulators is used to treat domestic animal (for example cat and dog) obesity; And the RUP3 receptor modulators is used for other domestic animal (for example edible-type animal, for example ox, chicken, fish etc.) of NAD or illness.Affiliated art ordinary person will be easy to understand the said purposes of said compound.
Combined therapy-prevention and treatment
In literary composition of the present invention, compound as described herein or its medical composition can be used for regulating the activity of disease described herein, symptom and/or illness that the RUP3 acceptor regulates.The instance of regulating the disease activity of RUP3 acceptor adjusting comprises prevention or treatment metabolic-related disorders, for example (but being not limited to) type i diabetes, type ii diabetes, improper glucose tolerance, insulin resistance, hyperglycemia, hyperlipidaemia, hypertriglyceridemia, hypercholesterolemia, hyperlipemia and X syndromes.Other instance of regulating the disease activity that the RUP3 acceptor regulates comprise through reduce ingestion of food, bring out satiety (meaning is glutted sensation), management of body weight increases, reduce body weight and/or influence that metabolism prevents or treatment of obesity and/or overweight so that the receptor reduces body weight and/or maintenance body weight.
Though The compounds of this invention comes into operation (meaning is a monotherapy) as unique active pharmaceutical reagent, they also can be used to treat disease/symptom described herein/illness with other pharmaceutical reagent combination (meaning is a combination treatment).Therefore; The present invention comprises the method that prevents and/or treats metabolic-related disorders or body weight associated conditions (for example obesity) on the other hand, comprises to the said individuality that prevents and/or treats of needs to throw and the The compounds of this invention (for example formula (I)) of treating effective dose and one or more other pharmaceutical reagents as described herein.
Can comprise antiobesity agent with the suitable pharmaceutical reagent that the The compounds of this invention combination is used, for example apolipoproteins-B secretory product/microsome tri-glyceride transfer protein (apo-B/MTP) suppressor factor, MCR-4 agonist, cholecystokinin-A (CCK-A) agonist, thrombotonin and norepinephrine reuptake inhibithors (for example sibutramine), type sympathetic nerve agent, β
3Adrenoceptor agonists, dopamine agonist (for example bromocriptine (bromocriptine)), melanotropin receptor analogs, cannaboid 1 receptor antagonist [SR141716N-(piperidines-1-yl)-5-(4-chloro-phenyl-)-1-(2 for example; The 4-dichlorophenyl)-4-methyl isophthalic acid H-pyrazole-3-carboxamide], melanochrome concentrating hormone antagonists, leptin (OB albumen), leptin analogue, leptin receptor agonist, galanin antagonist, lipase inhibitor (orlistat (tetrahydrolipstatin for example; Meaning is Orlistat)), appetite-inhibiting agent (for example Magainin (bombesin) agonist), neuropeptide-Y antagonist, Protirelin agent, trans-dehydroandrosterone or its analogue, glucocorticoid receptor agonist or antagonist, increase food factor acceptor antagonist, the conjugated protein antagonist of urotensin, glucagon-like peptide-1 receptor stimulant, CNTF (Tarrytown for example; NY and Procter & Gamble Company; Cincinnati; The Regeneron Pharmaceuticals of OH, the Axokine that Inc sells
TM), human cavy GAP-associated protein GAP (AGRP), Ge Ruilin receptor antagonist, histamine 3 receptor antagonists or inverse agonist, neuromedin U receptor stimulant, produce appetite-inhibiting agent (for example PHENTERMINE, SaH-42548 etc.), the anoretic (for example Wellbutrin) of sympathin.
Other antiobesity agent that comprises reagent mentioned above be common those who familiarize themselves with the technology know, it is perhaps common that those who familiarize themselves with the technology will easily understand according to this disclosure.
In certain embodiments, said antiobesity agent is selected from the group that is made up of orlistat, sibutramine, bromocriptine, racephedrine, leptin and pseudoephedrine.In another embodiment, The compounds of this invention and combination treatment are combined to come into operation with exercise and/or reasonable diet.
The category that should be appreciated that the combination treatment of The compounds of this invention and other antiobesity agent, appetite-inhibiting agent, anoretic and related reagent is not limited to the listed person of preceding text, and comprises and be used to treat any pharmaceutical reagent of overweight and obese individuals or any combination of medical composition in principle.
Except that antiobesity agent; Can be used for comprising the reagent that is used to treat metabolic-related disorders and/or its accompanying diseases with other suitable pharmaceutical reagent of The compounds of this invention combination; These diseases are (but being not limited to) congestive heart failure, type i diabetes, type ii diabetes for example, improper glucose tolerance, insulin resistance, hyperglycemia, hyperlipidaemia, hypertriglyceridemia, hypercholesterolemia, hyperlipemia, X syndromes, retinopathy, ephrosis and neuropathy.Prevent or treat the listed disease of one or more this paper to comprise one or more known pharmaceutical reagents in affiliated field of use; (for example shellfish is special type, comprises fenofibrate, bezafibrate, gemfibrozil, clofibrate etc. to belong to the medicine of medicine-sulfonylurea of mentioning below (but being not limited to), meglitinide, biguanides, alpha-glucosidase inhibitor, peroxisome proliferation-activated receptors-γ (meaning is PPAR-γ) agonist, Regular Insulin, insulin analog, HMG-CoA reductase inhibitor, reducing cholesterol; Bile acid chelating agent comprises QUESTRAN, cholestipol etc.; And nicotinic acid), anti-platelet agents (for example Frosst) and ADP receptor antagonist, comprise more than the Crow, ticlopidine etc.), angiotensin converting enzyme inhibitor, angiotensin ii receptor antagonist and adiponectin etc.According to an aspect of the present invention, The compounds of this invention can be used for and one or more the pharmaceutical reagent combination that belongs in the listed drug type of preceding text.
The category that should be appreciated that the combination treatment of The compounds of this invention and other pharmaceutical reagent is not limited to this paper, preceding text or hereinafter described, and comprises in principle and be used to prevent or any pharmaceutical reagent of treatment and metabolic-related disorders diseases associated, symptom or illness or any combination of medical composition.
Some embodiments of the invention comprise prevention or treat the method for disease as herein described, illness, symptom or its complication; It comprises to the individuality of said prevention of needs or treatment throws and the The compounds of this invention and at least a pharmaceutical reagent that is selected from the group that is made up of following material of treating effective dose (amount or dose): (for example shellfish is special type, comprises fenofibrate, bezafibrate, gemfibrozil, clofibrate etc. for the medicine of sulfonylurea, meglitinide, biguanides, alpha-glucosidase inhibitor, peroxisome proliferation-activated receptors-γ (meaning is PPAR-γ) agonist, Regular Insulin, insulin analog, HMG-CoA reductase inhibitor, reducing cholesterol; Bile acid chelating agent comprises QUESTRAN, cholestipol etc.; And nicotinic acid), anti-platelet agents (for example Frosst) and ADP receptor antagonist, comprise more than the Crow, ticlopidine etc.), angiotensin converting enzyme inhibitor, angiotensin ii receptor antagonist and adiponectin.In certain embodiments, method of the present invention comprises independently come into operation The compounds of this invention and pharmaceutical reagent.In other embodiments, come into operation jointly The compounds of this invention and pharmaceutical reagent.
Can comprise sulfonylurea with the common suitable pharmaceutical reagent that uses of The compounds of this invention.Said sulfonylurea (SU) is to promote the medicine from the pancreatic beta cell excreting insulin through transmitting the insulin secretion signal via SU acceptor in the cytolemma.The instance of sulfonylurea comprises glyburide (glyburide), glipizide (glipizide), known other sulfonylurea of gsh (glimepiride) and affiliated field.
Can comprise meglitinide with the common suitable pharmaceutical reagent that uses of The compounds of this invention.Meglitinide be one type the representative novel insulin secretagogue the benzyl acid derivative.Said reagent target is post-prandial hyperglycemia and is showing and the comparable effectiveness of sulfonylurea aspect the minimizing HbAlc.The instance of Ge Lienai comprises repaglinide (repaglinide), Starsis (nateglinide) and known other Ge Lienai in affiliated field.
Can comprise biguanides with the common suitable pharmaceutical reagent that uses of The compounds of this invention.Biguanides is one type and promotes anaerobic glycolysis, increases in the peripheral tissues insulin sensitivity, suppresses from intestinal absorption glucose, suppresses the liver starch heteroplasia and suppress the medicine of Fatty Acid Oxidation.The instance of biguanides comprises: phenformin (phenformin), N1,N1-Dimethylbiguanide (metformin), the known biguanides of W-37 (buformin) and affiliated field.
Can comprise alpha-glucosidase inhibitor with the common suitable pharmaceutical reagent that uses of The compounds of this invention.Digestive ferment in alpha-glucosidase inhibitor competitive inhibition pancreas or the small intestine, for example AMS, maltin, limit dextrinase, sucrase etc.The reversible inhibition of alpha-glucosidase inhibitor slows down, weakens or even lowering blood glucose level through the digestion that postpones starch and sugar.Voglibose (voglibose)), the known alpha-glucosidase inhibitor of miglitol (miglitol) and affiliated field the instance of alpha-glucosidase inhibitor comprises acarbose (acarbose), N-(1,3-dihydroxyl-2-propyl group) volt row amine (valiolamine) (generic name:.
Can comprise peroxisome proliferation-activated receptors-γ (meaning is PPAR-γ) agonist with the common suitable pharmaceutical reagent that uses of The compounds of this invention.Peroxisome proliferation-activated receptors-gamma agonist is represented the compound of a Class Activation nuclear receptors PPAR's-γ and is therefore regulated the insulin response gene transcription that relates to the manufacturing of control glucose, conveying and utilization.The reagent of said classification also promotes the adjusting of fatty acid metabolism.The instance of PPAR-gamma agonist comprises rosiglitazone (rosiglitazone), pioglitazone (pioglitazone), safe this lucky tower this (tesaglitazar), its ketone of promise lattice (netoglitazone), GW-409544, the known PPAR-gamma agonist of GW-501516 and affiliated field.
Can comprise the HMG-CoA reductase inhibitor with the common suitable pharmaceutical reagent that uses of The compounds of this invention.The HMG-CoA reductase inhibitor also is the reagent that is called his spit of fland (Statin) compound, and statins belongs to one type through suppressing the medicine that HMG CoA (HMG-CoA) reductase enzyme reduces blood cholesterol levels content.The HMG-CoA reductase enzyme is the biosynthetic rate-controlling enzyme of SUV.He reduces serum LDL concentration and is responsible for from blood, removing LDL through the activity to the adjusted ldl receptor in the spit of fland.Some representative instances of statins comprise rosuvastatin (rosuvastatin); Pravastatin (pravastatin) and its sodium salt; SV (simvastatin); Lovastatin (lovastatin); Atorvastatin (atorvastatin); Fluvastatin (fluvastatin); Cerivastatin (cerivastatin); Rosuvastatin; Pitavastatin (pitavastatin); " super he spit of fland (superstatin) " of BMS and the known HMG-CoA reductase inhibitor in affiliated field.
Can comprise special type of shellfish with the common suitable pharmaceutical reagent that uses of The compounds of this invention.Shellfish specialization compound belongs to one type of medicine that reduces blood cholesterol levels content through the synthetic and secretion and the activation LPL of tri-glyceride in the inhibition liver.The special class of known shellfish can activate by peroxisome proliferator-activated acceptor and bring out LPL and express.The special examples for compounds of shellfish comprises: bezafibrate (bezafibrate); Sgd-24774 (beclobrate); WAC-104 (binifibrate); Xi Pubeite (ciplofibrate); S-8527 (clinofibrate); Clofibrate (clofibrate); Clofibric acid; Etofibrate (etofibrate); Fenofibrate (fenofibrate); Gemfibrozil (gemfibrozil); Nicofibrate (nicofibrate); Pirifibrate (pirifibrate); Ronifibrate ronifibrate); Simfibrate (simfibrate); Etophylline Clofibrate (theofibrate) and the known Bei Te in affiliated field.
Can comprise angiotonin saccharase (ACE) suppressor factor with the common suitable pharmaceutical reagent that uses of The compounds of this invention.Angiotonin converting enzyme inhibitor class belongs to one type through suppressing the medicine that the angiotonin saccharase comes part lowering blood glucose level and brings high blood pressure down.The instance of angiotonin converting enzyme inhibitor class comprises: captopril (captopril); Enalapril (enalapril); DU-1219 (alacepril); Delapril (delapril); Ramipril (ramipril); Lisinopril (lisinopril); Imidapril (imidapril); Zinadril Briem (benazepril); SQ-29852 (ceronapril); Yipingshu (cilazapril); Enalaprilat (enalaprilat); Fosinopril (fosinopril); Order Wei Puli (moveltopril); Perindopril (perindopril); Quinapril (quinapril); Spirapril (spirapril); Temocapril (temocapril); The known angiotonin converting enzyme inhibitor of Trolapril (trandolapril) and affiliated field.
Can comprise angiotensin ii receptor antagonist with the common suitable pharmaceutical reagent that uses of The compounds of this invention.The angiotensin ii receptor antagonist target is angiotensin-ii receptor subtype 1 (meaning is AT1) and shows hypertensive beneficial effect.The instance of angiotensin ii receptor antagonist comprises the known angiotensin ii receptor antagonist of losartan (with its potassium salt form) and affiliated field.
Other for the listed treatment of diseases of one or more this paper comprise use under the known pharmaceutical reagent in field, belong to the medicine of mentioning below (but being not limited to): Amylin agonist (for example tripro-amylin (pramlintide)), insulin secretion stimulators (for example GLP-1 agonist, incretin analogue (exendin-4), Regular Insulin short give birth to skin (insulinotropin) (NN2211), dipeptide peptidase suppressor factor (dipeptyl peptidase inhibitor) (for example NVP-DPP-728), ACAT inhibitors (for example ezetimibe (Ezetimibe), according to Fu Ximibei (eflucimibe) and similar compound), cholesterol absorption inhibitor (for example ezetimibe, Pamaqueside (pamaqueside) and similar compound), cholestery ester transfer protein inhibitors (for example CP-529414, JTT-705, CETi-1 and similar compound), microsome tri-glyceride transfer protein inhibitor (for example Ai Puli safe (implitapide) and similar compound), Cholesterol Regulating Agents (for example NO-1886 and similar compound), bile acide regulator (for example GT103-279 and similar compound) and Supraene synthetic inhibitor.
The Supraene synthetic inhibitor belongs to one type and synthesizes the medicine that reduces blood cholesterol levels content through suppressing Supraene.The instance of Supraene synthetic inhibitor class comprises: (S)-and α-[two [2,2-dimethyl--1-oxopropoxy] methoxyl group] phosphinyl]-the known Supraene synthetic inhibitor of 3-phenoxy benzene fourth sulfonic acid potassium salt (BMS-188494) and affiliated field class.
According to the present invention, said combination can be used through following method: each active constituent is mixed with the acceptable supporting agent of physiology mentioned above, vehicle, tackiness agent, thinner etc. together or respectively and with said mixture with oral or non-oral the coming into operation of medical composition form.When with formula (I) compound or its mixture and the dispensing of other active compound combined therapy, can said healing potion be deployed into simultaneously or the independent medical composition of administration simultaneously not, perhaps said therapeutical agent can be used as single compsn administration.
Other effectiveness
Another target of the present invention relates to radiolabeled formula (I) compound; They not only can be used for radiophotography (radio-imaging) and also can be used for analyzing in vitro and in vivo; Locate with quantification tissue samples (comprising the mankind) in RUP3, and discern the RUP3 part through the combination that suppresses radio-labeled compound.Another target of the present invention is the novel RUP3 analytical method that exploitation comprises said radio-labeled compound.
The subgenus of isotope-labeled formula (I) compound and any this paper is contained in the present invention, and for example (but being not limited to) formula (Ia) is to formula (IIIo)." isotropic substance " or " radio-labeling " compound is and identical compound disclosed herein, but in fact one or more atoms are by nucleidic mass or total mass number and general in fact being seen nucleidic mass or different atomic substitutions or the replacements of total mass number.Can combine the suitable radionuclide of The compounds of this invention to include, but is not limited to:
2H (also being write as the D of deuterium),
3H (also being write as the T of tritium),
11C,
13C,
14C,
13N,
15N,
15O,
17O,
18O,
18F,
35S,
36Cl,
82Br,
75Br,
76Br,
77Br,
123I,
124I,
125I with
131I.To depend on the application-specific of those radio-labeled compounds in conjunction with the radionuclide in this radio-labeled compound.For example, as far as in vitro RUP3 receptor marker and competition assays, in conjunction with
3H,
14C,
82Br,
125I,
131I,
35The compound of S is generally the most useful.For radiophotography is used
11C,
18F,
125I,
123I,
124I,
131I,
75Br,
76Br or
77Br will be the most useful generally.
Should be appreciated that " radio-labeling " or " compound of mark " is the The compounds of this invention that has combined at least a radionuclide; In certain embodiments, said radionuclide be selected from by
3H,
14C,
125I,
35S with
82The group that Br forms.
Some isotope-labeled compound of the present invention is useful in compound and/or matrix organization's distribution inspection.In certain embodiments, radionuclide
3H and/or
14The C isotropic substance is useful in these researchs.In addition, (promptly with deuterium for example
2H) therefore heavy isotope replacement department produces the particular treatment advantage that results from than greater metabolic stability (for example increasing in vivo transformation period or the minimizing dosage of wanting) is preferred in some cases also.Compound isotopically labelled of the present invention generally can prepare with the mode that the heterotope labelled reagent replaces isotope labeling reagent through the program that instance disclosed of following scheme that is similar to preceding text and hereinafter.Other useful compound method hereinafter is discussed.In addition, should be appreciated that the whole atoms that are shown in the The compounds of this invention can be the isotropic substance that the most often occurs of said atom or rarer ri or non radioactive isotope.
Ri is attached to synthesis method in the organic cpds can be applicable to The compounds of this invention and in affiliated field, is known by people.For example, the compound method that is attached in the target molecule of these tritiums with activity level is following
A produces the product of high specific activity usually and needs halogenation or undersaturated precursor with tritium gas catalytic reduction one this program.
B with Peng Qinghuana [
3H] reduction-this program is quite economical and need contain for example reductibility functional groups' such as aldehyde, ketone, lactone, ester precursor.
C with lithium aluminum hydride [
3H] reduction-this program provides the product that is almost theoretical specific activity.It also need contain for example reductibility functional groups' such as aldehyde, ketone, lactone, ester precursor.
D tritium gas exposure mark-this program comprises suitably is being exposed under the tritium gas precursor that contains exchangeable protons in the presence of the catalyzer.
E with methyl iodide [
3H] come N-methylate-this program be generally used for through with the high specific activity methyl iodide (
3H) handle suitable precursor prepare O-methyl or N-methyl (
3H) product.This method generally allows high specific activity, for example about 70-90C
1/ mmol.
With activity level
125The compound method that I is attached in the target molecule comprises:
A Sandmeyer changes into the diazonium salt of (for example) a tetrafluoro borate with its similar reaction-this program with arylamine or assorted arylamine, and uses Na subsequently
125I converts it into
125The tokenized compound of I.Zhu, D-G and its co-worker be at J Org Chem2002, and 67, reported a representative program among the 943-948.
The ortho position of B phenol
125Iodate-this program makes
125I combines with phenol at the ortho position, and like Collier, T L and its co-worker report among the S264-S266 at J labelled Compd Radiopharm 1999,42.
C aryl bromide and heteroaryl bromine with
125I exchange-this method is generally one two step procedure.The first step for example is to use, and the Pd catalyzed reaction [is Pd (Ph
3P)
4] or through lithium aryl or heteroaryl lithium at tri haloalkyl tin or six alkyl, two tin [(CH for example
3)
3SnSn (CH
3)
3] make aryl bromide or heteroaryl bromine change into corresponding trialkyltin midbody under existing.Bas, M-D and its co-worker have reported generation list procedure at J Labelled Compd Radiopharm 2001,44 among the S280-S282.
The RUP3 compound of the present invention of labelled with radioisotope can be used for screening test and discerns/assessing compound.In short, can estimate the ability that new compound (being test compounds) synthetic or that identify reduces " radiolabeled The compounds of this invention " and RUP3 receptors bind.Therefore, test compounds combines the ability of RUP3 acceptor directly relevant with its binding affinity with " radiolabeled The compounds of this invention " competition.
Tagged compound of the present invention and RUP3 receptors bind.The IC of tagged compound described in embodiment
50Less than about 500 μ M, tagged compound IC described in another embodiment
50Less than about 100 μ M, the IC of tagged compound described in another embodiment
50Less than about 10 μ M, the IC of said tagged compound In yet another embodiment
50Less than about 1 μ M, and the IC of tagged compound described in another embodiment
50Less than about 01 μ M.
One of ordinary skill in the art based on (especially) to the review of this patent file can understand other purposes of the acceptor that discloses and method.
As will understand.The step of the inventive method need not carried out any specific times or carry out with any particular order.One of ordinary skill in the art are when check following illustrative and nonrestrictive instance, and other target of the present invention, advantage and novel feature are obvious.
Instance
It is to be limited in the details of these instances for further explain the present invention rather than with the present invention that said instance is provided.
The 96 orifice ring AMP films check of RUP3
Material
1) available from the adenylate cyclase enzyme activation of Perkin Elmer flicker plate test kit-96 hole (SMP004B) with provide with test kit
125I tracer agent (NEX130) places box to preserve at refrigerator, and the flicker plate is exposed under the light.
2) phosphocreatine-SigmaP-7936
3) creatine phosphokinase-Sigma C-3755
4)GTP-Sigma?G-8877
5)ATP-SigmaA-2383
6)IBMX-Sigma?I-7018
7) Hepes-1M distilled water solution-Gibco#15630080
8) MgCl
2-SigmaM-1028-1M solution
9) NaCl-Sigma-S6546-5M solution
10) Bradford protein test kit-Biorad#5000001
11)Proclin?300-Sigma#4-8126
Binding buffer liquid-filter and be stored in the refrigerator through 45-micron Nalgene strainer.All damping fluids and film should keep low temperature (in ice bucket) when testing.
20mMHepes，pH?741mMMgCl
2?100mMNaCl
2 * regeneration damping fluid (preparing in the binding buffer liquid)
20mM phosphocreatine (102gm/200mL binding buffer liquid)
20 unit creatine phosphokinases (4mg/200mL)
20 μ MGTP (in binding buffer liquid, be mixed with 1046mg/mL and add 200 μ L/200mL)
02mMATP(22.04mg/200mL)
100mMIBMX (at first 444mgIBMX is dissolved among the 1mL100%DMSO and then it is all added in the 200mL damping fluid)
Can the regeneration damping fluid be divided into 40-45mL part (in the 50mL sterile test tube) and keep freezing and reach 2 months.Only test tube was placed the beaker that the water under the room temperature is housed said regeneration damping fluid is thawed the same day in check.
A. testing procedures
1) with Matrix 1,250 8 passage pipettors 50 μ L regeneration damping fluid is moved in all 96 holes.
2) 5 μ LDMSO are moved in the 1st row and the 11st and 12 row.
3) with this tab sequencial 50 μ L cAMP reference liquids are moved in the 11st and 12 row: capable 50 picomole of A/hole; Capable 25 picomole of B/hole; Capable 125 picomole of C/hole, capable 5 picomole of D/hole, capable 25 picomole of E/hole; Capable 1.25 picomole of F/hole, capable 05 picomole of G/hole and capable 0 picomole of H/hole (being merely damping fluid).
4) use following dilution flow process from each hole of diluted chemical compound plate, to shift out 5 μ L compounds to be used for IC
50.
H hole: 400 μ M compounds (ultimate density of compound in the reaction mixture=5/100 * 400 μ M=20 μ M)
G hole: 1: 10 diluent in H hole (being the 5 μ L compounds+45 μ L100%DMSO in H hole) (ultimate density=2 μ M)
F hole: 1: 10 diluent in G hole (ultimate density=0 2 μ M)
E hole: 1 10 diluents in F hole (ultimate density=0.02 μ M)
D hole: 1: 10 diluent in E hole (ultimate density=0 002 μ M)
C hole: 1 10 diluents in D hole (ultimate density=0.0002 μ M)
B hole: 1: 10 diluent in C hole (ultimate density=0 00002 μ M)
A hole: 1 10 diluents in B hole (ultimate density=0 000002 μ M)
IC
50Or EC
50Repeat three times.Therefore can set up a flicker plate and handle 3 kinds of compounds (promptly the 2nd, 3 and 4 row are used for compound # 1, and the 5th, 6 and 7 row are used for compound # 2 and the 8th, 9 and 10 row are used for compound #3).
5) in the institute of the 2nd to 10 row is porose, add 50 μ LRUP3 films.(before the check beginning, the frozen film granule (through not containing the expression plasmid cells transfected of RUP3 sequence) of RUP3 and CMV all is suspended in the binding buffer liquid, the film of general 1 plate is with 1mL binding buffer liquid.Said film is stored in the ice all the time, and uses polytron (Brinkmann polytron, model #PT-3100) (6-7 shelves, keep 15-20 second) to obtain the film suspension-s of homogeneous.Through Bradford protein test kit, use specification sheets that said test kit provides and the standard of using said test kit to provide to measure protein concn as a reference.With the protein concn of binding buffer liquid adjustment film, to reach 50 μ L films=15 μ g protein (i.e. 0 3mg/mL protein).
6) in the 1st row, in A, B, C and D hole, add 50 μ LRUP3 films.In E, F, G and H hole, add 50 μ LCMV films (the CMV film is identical with the protein concn of RUP3 film).
7) at room temperature cultivate 1 hour, on a rotation table shake, stir simultaneously.Use sheet metal cover during vibration.
8) after 1 hour, 100 μ L in the detection damping fluid that (in whole 96 holes) interpolation flicker plate test kit is provided
125The I marking agent adds proclin, in the following manner preparation:
Every 10mL moves in each flicker plate: 100mL detects damping fluid+1mL
125I+0 2mL Proclin (said proclin helps to stop generation cAMP).If the more a spot of detection buffer solution mixture of the less just preparation of plate number.
9) on a rotation table shake, said flicker plate was vibrated 2 hours, with plumbous laminated covering plate.
10) the plastics film sealer that is provided with flicker plate test kit seals plate.
11) use TRILUX 1450 Microbeta telltales that said plate is counted.Which counting scheme the demonstration mouth (door) of noting telltale to confirm to use.
12) the not fusion RUP3, the IC that check according to 96 hole cAMP films
50EC
50, analytical data on Arena Database, and compound number and compound concentration must be imported by the user.
B. film cyclase standard
1) SNR
Acceptable RUP3 SNR can change 4 to 6.The original cpm (cpm) of RUP3 is approximately 1800 to 2500 and the original cpm of CMV is 3500 to 4500.Said original cpm (or final every hole cAMP picomole number) can not be outside typical curve, and the A hole (50 picomole/hole) of the curve that should not be near the mark and H hole (no cAMP).Generally speaking, the cAMP picomole number that the RUP3 acceptor produces is approximately 11 to 13 picomole/hole (every hole 15 μ g protein), and CMV produces is 2 to 3 picomole/hole (every hole 15 μ g protein).
2) typical curve:
Slope should be linear and error bar repeated sample should be very little.Acceptor and CMV control group can not exceed standard curve range mentioned above.If the acceptor control group exceeds the vertex of typical curve, promptly protein repeated experiments still less must be used so in 50 picomole/hole or higher.Yet the RUP3 film of of short duration transfection (every 15cm plate 10 μ gDNA use 60 μ L Lipofectamine, and after transfection 24 hours preparation films) is not found said situation.
3) IC
50Or EC
50The top of curve should be 100% (+or-20%) RUP3 film control group, and the bottom should drop to 0 (or until 20%).The standard error of three replications should be+or-10%.
C. stimulate the cAMP in the HIT-T15 cell
HIT-T15 (ATCC CRL#1777) is that a kind of immortalization hamster insulin-producing cells is.These cell expressings RUP3 and therefore can be used for assessing the RUP3 part and reach receptor for stimulating or suppress cAMP cumulative ability via its endogenous body surface.In this check, cell grows to 80% and converges and it is distributed in to come in one the 96 hole flicker plate (50,000 cells/well) via " check of cAMP flicker plate " (NEN, Cat#SMP004) detection cAMP.Briefly, cell is placed the hole of containing mediator (test ligand of the concentration of wanting) or 1 μ M Buddhist SCH (forskolin), said hole scribbles anti--cAMP antibody.The Buddhist SCH is a kind of direct activation agent of adenylate cyclase and serves as the positive control that stimulates cAMP in the HIT-T15 cell.All conditions repeated test three times.Cultivate 1 hour to allow stimulating cAMP, will contain then
125The detection mixture of I-cAMP adds in each hole and said plate was cultivated 1 hour again.It is unconjugated to remove then to aspirate said hole
125I-cAMP.Use Wallac Microbeta telltale to detect bonded
125I-cAMP.Through relatively measuring the cAMP amount in each sample with typical curve, said typical curve is to obtain through the cAMP that inserts concentration known in some holes on said plate.
D. stimulate insulin secretion in the HIT-T15 cell
Known when the glucose concn in the substratum when 3mM changes to 15mM, stimulate the cAMP in the HIT-T15 cell to cause that insulin secretion increases.Therefore, also can test the ability of glucose dependency insulin secretion (GSIS) in the RUP3 ligand stimulation HIT-T15 cell.In this check, in one 12 orifice plate, cultivated 30,000 cells in every hole 2 hours in containing 3mM glucose and not containing in the substratum of serum.Change substratum then, the substratum of 3mM or 15mM glucose is accepted to contain in the hole, and said substratum all contains mediator (DMSO) or the RUP3 part of wanting concentration to some extent under two kinds of situation.The substratum that some holes are accepted to contain 1 μ M Buddhist SCH is as positive control.All conditions repeated test three times.Cell culture 30 minutes and use are measured the amount of insulin that is secreted in the substratum available from the test kit of Peninsula Laboratories (Cat#ELIS-7536) or Crystal Chem Inc (Cat#90060) through ELISA.
E. stimulate insulin secretion in the isolated rat pancreas islet
The same with the HIT-T15 cell, known when the glucose concn in the substratum when 60mg/dl changes to 300mg/dl, stimulate the cAMP in the isolated rat pancreas islet to cause that insulin secretion increases.RUP3 is the endogenous expression GPCR in the insulin-producing cells of rat Langerhans islet.Therefore, also can test the ability of RUP3 part at rat Langerhans islet culture moderate stimulation GSIS.This check is carried out as follows:
A uses dissecting microscope to select 75-150 pancreas islet equivalent (IEQ) for each condition for surveys.Cultivation overnight in the low dextrose substratum.(optional)
B is divided into 3 increments originally with pancreas islet, every this 25-40 of increment pancreas islet equivalent.It is transferred to one 6 40 μ m meshes in the orifice bore does not have on the mycetocyte filter screen, has 5mL low (60mg/dl) glucose Krebs-Ringers damping fluid (KRB) examination medium in the hole.
C is at 37 ℃ and 5%CO
2Under cultivate 30 minutes (if needing 1 hour so) without step overnight.The positive control of RIA keeps supernatant so if desired.
The filter screen that D will have a pancreas islet is transferred to every hole to be had in the new hole of 5mL low dextrose KRB.This is to cultivate in advance for the second time and is to be used for removing resistates or taking Regular Insulin out of from substratum.Cultivated 30 minutes.
E with filter screen transfer to have 4 or the next batch hole of 5mL low dextrose KRB (low 1) in.Cultivated 30 minutes down at 37 ℃.Supernatant is collected in the low associativity Vestolen PP 7052 test tube and is kept low temperature, said test tube by mark in advance for identification.
F transfers to filter screen in the high glucose hole (300mg/dl is equivalent to 16 7mM).Cultivate and collect supernatant as aforementioned.Pancreas islet in low dextrose in the rinsing filter screen removes residual Regular Insulin.If collect rinsing liquid to be used for analysis, each condition is all used a rinsing hole (being that each condition is done three times) so.
G. filter screen is transferred in the final hole (low 2) with low dextrose examination medium.Like aforementioned cultivation and collection supernatant.
H keeps the cryogenic while, under 4-8 ℃, removes the little pancreas islet/pancreas islet piece that spills the 40mm mesh in 5 minutes with the 1800rpm centrifuged supernatant.With almost removing and be assigned in duplicate in the low associativity test tube that mark is crossed in advance less than all little pancreas islet/pancreas islet of 05-1mL.In that < 20 ℃ of following refrigerated storages are up to measuring insulin concentration.
I such as preceding text or use their rat insulin RIA (Cat#RI-13K) to carry out insulin assay by regular service by Linco Labs.
A. the RT-PCR that RUP3 expresses in the human tissue analyzes (Figure 1A).
Measure the tissue distribution of RUP3 with RT-PCR.The oligonucleotide that is used for PCR has following sequence:
ZC47:5 '-CATTGCCGGGCTGTGGTTAGTGTC-3 ' (forward primer), (SEQ ID NO:3);
ZC48:5 '-GGCATAGATGAGTGGGTTGAGCAG-3 ' (reverse primer), (SEQ ID NO 4);
And (MTC is Clontech) as template (each pcr amplification uses 1ngcDNA) to use human many tissue cDNA plate.Analyze 22 (22) individual human tissues.Pressing following order uses Platinum PCR SuperMix (life Technologies, Inc is with manufacturer's instructions) to carry out PCR in 50 μ l reaction systems: step 1, and 95 ℃ are following 4 minutes; Step 2,95 ℃ are following 1 minute; Step 3,60 ℃ are following 30 seconds; Step 4,72 ℃ are following 1 minute; And step 5,72 ℃ are following 7 minutes.Step 2 to step 4 is repeated 35 times.
Gained PCR reactant (15 μ l) loaded on analyze the RT-PCR product on 1.5% sepharose, represent specific 466 base pair dna fragments of RUP3 from the cDNA specific amplification in pancreas source.The low expression also obviously arranged in the brain subprovince.
B. the eDNA Dot blot that RUP3 is expressed in the human tissue is analyzed (Figure 1B).
The result that RT-PCR analyzes gained further is confirmed in the analysis of cDNA Dot blot.In this check, make contain from the dot blot (Clontech) of 50 kinds of human tissue cDNA with have the sequence that is derived from human RUP3
32The hybridization of P-labeled DNA probe.In pancreas and fetus liver, see hybridization signal, show these tissue expressions RUP3.Do not detect remarkable expression in other tissue of being analyzed.
C. analyze RUP3 (Fig. 1 C) with stripped human youth's lattice Han Shi (Langerhans) pancreas islet by RT-PCR.
Further analyze RUP3 with stripped human youth's lattice Han Shi pancreas islet by RT-PCR and demonstrate RUP3 and firmly be expressed in the islet cells, but firmly be not expressed in the check sample.
D analyzes RUP3 by RT-PCR with rat source cDNA and expresses (Fig. 1 D)
Further analyzing RUP3 by the RT-PCR technology with rat source cDNA expresses.The tissue cDNA that is used for this check is removed hypothalamus and pancreas islet cDNA and is prepared voluntarily available from Clontech.Before checking R UP3 expresses, analyze house-keeping gene (house-keeping gene) GAPDH via contrast RT-PCR and come the concentration of each cDNA sample of stdn.The oligonucleotide that is used for PCR has following sequence:
Forward rat RUP3 (" rRUP3 "): 5 '-CATGGGCCCTGCACCTTCTTTG-3 ' (SEQ ID NO:5);
Reverse rRUP3:5 '-GCTCCGGATGGCTGATGATAGTGA-3 ' (SEQ ID NO.6);
Press following order and in 50 μ l reaction systems, use Platinum PCR SuperMix (life Technologies, Inc.; With manufacturer's instructions) execution PCR: step 1,95 ℃ are following 4 minutes; Step 2,95 ℃ are following 1 minute; Step 3,60 ℃ are following 30 seconds; Step 4,72 ℃ are following 1 minute; And step 5,72 ℃ are following 7 minutes.Step 2 to step 4 is repeated 35 times.
Gained PCR reactant (15 μ l) loaded on analyze the RT-PCR product on 15% sepharose, and represent specific 547 base pair dna fragments of rat RUP3, show and human similarly express spectra from the cDNA specific amplification in pancreas source.What arouse attention especially is in stripped pancreas islet and hypothalamus, to see firm expression.
The RUP3 protein expression is confined to the β cell lineage (Fig. 2) of pancreas islet.
A. in rabbit, prepare the anti-RUP3 antibody of polyclone (Fig. 2 A).
Apparatus has the antigen peptide of the sequence that comes from rat RUP3 (" rRUP3 ") to make the rabbit immunity.Said peptide sequence is RGPERTRESAYHIVTISHPELDG and has 100% identity with mouse RUP3 in the respective regions.Before to the rabbit injection, make the N end of this antigen peptide combine cysteine residues to promote KLH crosslinked.Test gained antiserum(antisera) (" anti-rRUP3 ") and corresponding preimmune serum (" preceding rRUP3 ") are to the immunoreactivity (1 to 4 band) of mouse RUP3 in the immunoblotting check.In this check, the GST-RUP3 fusion rotein is discerned by anti-rRUP3 antiserum(antisera) (4 band) easily, and is difficult for by preimmune serum (2 band) identification., said immunoblotting check can effectively eliminate immunoreactivity signal (6 band) when carrying out in the presence of excessive antigen peptide.
B. the Regular Insulin of pancreas islet produces the RUP3 expression (Fig. 2 B) in the β cell.
Imbed in the OCT embedding medium with the perfusion pancreas in rat of 4% Paraformaldehyde 96 (PFA) among the PBS and with it.Be made into 10 microns sections, be fixed on the slide glass, and, use subsequently with the anti-tame rabbit igg of optical dye Cy-3 conjugated donkey and carry out the dyeing second time with preceding rRUP3 (Fig. 2 B, a district) or anti--rRUP3 antiserum(antisera) (Fig. 2 B, c and e district) immunostaining.In first dyeing, also use monoclonal anti insulin antibody (SantaCruz; Fig. 2 B; B and d district) to each common immunostaining of cutting into slices; Use subsequently with the anti-mouse IgG of FITC conjugated donkey or with goat anti hyperglycemic-glycogenolytic factor antibody (SantaCruz, Fig. 2 B, f district) with the anti-goat IgG of the donkey of FITC coupling and dye for the second time.Inspection immunofluorescence signal under fluorescent microscope.Find that RUP3 is expressed in the insulin-producing cells (c and d district), do not produce in the cell (e and f district) but be not expressed in hyperglycemic-glycogenolytic factor.These digital proofs RUP3 is expressed in the β cell and is not expressed in the rat Langerhans islet β cell., the RUP3 of research mice pancreatic section obtains similar results when expressing.
RUP3 functionally active (Fig. 3) in vitro.
Confirmed that RUP3 is through coming cAMP production with following material cotransfection 293 cells: (1) CRE-luciferase reporter gene; The ability that its moderate stimulation Photinus pyralis LUC produces depends on the cAMP that increases in the cell, and the expression plasmid of (2) coding human form RUP3 (Fig. 3 A).Should note producing uciferase activity seldom with the cell of expression plasmid (" CMV " among Fig. 3 A) cotransfection that does not contain the RUP3 sequence, but with at least 10 times of the uciferase activity increases of the expression plasmid cells transfected of the RUP3 (Fig. 3 A " RUP3 ") that encodes.CAMP production when this phenomenon points out that RUP3 is in being introduced in 293 cells.This specific character of RUP3 is striden species and is kept, because hamster RUP3 stimulates luciferase cAMP to produce (Fig. 3 B) to be similar to when being incorporated into 293 cells to the described mode of human RUP3.
What confirm is when cAMP in the insulin-producing cells of pancreas increases, and these cells demonstrate excreting insulin when glucose concn rises ability strengthens.For testing RUP3 whether the release of enhanced glucose dependency Regular Insulin can be provided, use the retrovirus that contains human RUP3 to produce the Tu6 cell of expressing high-level RUP3.The Tu6 cell produces Regular Insulin, but the RUP3 that does not express considerable level, and the Tu6 cell does not generally show the increase that Regular Insulin discharges when the glucose that exists in the substratum increases.Shown in Fig. 3 C, still can produce Regular Insulin with the Tu6 cell of the contrast virus transduction that does not contain acceptor, but not increase when the insulin secretion when 1mM becomes 16mM of the glucose concn in the substratum.In contrast, the Tu6 cell with the retrovirus transduction that contains RUP3 shows significant glucose dependency insulin secretion (Fig. 3 C).
The RUP3 agonist is to the in vivo effect of glucose stable state in the rat.
A. oral glucose tolerance property testing (oGTT)
Male Sprague Dawley rat fasting 15 hours and the random packet (n=6) that body weight is about 200g-250g accepts 3,10 or the RUP3 agonist (compd A 194, A214 or D4) of 30mg/kg.Via tube feed pin oral delivery compound (oral, volume 3mL/kg).In the time 0, (Elite XL is Bayer) and to rat come into operation mediator (20% hydroxypropyl-beta-cyclodextrin) or test compounds to assess glucose level with blood glucose meter.After the test compounds that comes into operation 30 minutes, assess glucose level once more, and with the dosage of 2g/kg to the oral Vadex that comes into operation of rat.The measuring blood when 30min after this time, 60min and 120min.Table 8 shows the average inhibition per-cent of each test compounds glucose drift, gets the MV of six animals of said treatment group.These results prove, are exciting back RUP3 agonist (compd A 194, A214 and D4) lowering blood glucose with glucose.
The average inhibition % of table 8 glucose drift
| Compound | Glucose inhibition % (dosage, mg/kg) |
| |
5％，(30) |
| A214 | 33％，(10) |
| D4 | 12％，(30) |
The generation of Tu6/RUP3 stable cell lines
In order to produce the Tu6 cell of high level expression RUP3, generate retrovirus with RUP3 expression cassette.Concise and to the point, with the RUP3 encoding sequence be cloned into retroviral vector pLNCX2 (Clontech, Cat#6102-1) in.(Clontech, K1060-D), and the guide that uses PT-67 producer to provide is set up stable cell lines with two preferendum (amphotropic) the package cell line PT-67 of parent vector pLNCX2 or pLNCX2/RUP3 transfection then to use Lipofectamine.According to manufacturer's explanation, obtain to contain retroviral supernatant through from the gained stable cell lines, collecting substratum.Then through in containing the 1mL virus supernatant/9mL culture medium solution of 40 μ g/mL polybrenes, cultivating the Tu6 cell that made retroviral infection place a 10cm dish in 24 hours.Then change medium into contain 300 μ g/mLG418 substratum.G418-resistance clone cell finally produces by means of being present in the neomycin resistance gene box in the pLNCX2 carrier, shows that thus retrovirus successfully is incorporated in the Tu6 genome.Confirm that with the Northern blotting RUP3 is expressed in the Tu6/RUP3G418-resistance group.
Instance 7
Insulin secretion, the Tu6 stability series
Be to measure the insulin secretion of rodent insulin-producing cells system, at first at serum-free, lack culturing cell overnight in the substratum of glucose.The next morning, again cell is positioned in the same medium that is supplemented with 1mM or 16mM glucose.Cultivate after 4 hours, collect this substratum and analyze insulin content with rat insulin enzyme immunity inspection (EIA) system (Amersham Pharmacia Biotech, Cat#RPN 2567).Generally, use the multiple diluent of sample substratum to test to guarantee that sample measurement is positioned at (using the pancreas islet of known quantity usually to produce) boundary of the typical curve of manufacturer's recommendation.
The receptors bind check
Except that method as herein described, the method that another kind is used for the evaluation test compound is the binding affinity of mensuration and RUP3 acceptor.Such check generally needs the radioactive mark ligand of RUP3 acceptor.The known ligand that does not use the RUP3 acceptor and its radioactively labelled substance, available radio-labeling formula (I) compound and use it for the evaluation test compound and the check of RUP3 receptor affinity in.
Can radiolabeled RUP3 compound of the present invention be used for differentiating/screening test of assessing compound.In short, can estimate the ability that new compound (being test compounds) synthetic or that newly identify reduces " radiolabeled The compounds of this invention " and RUP3 receptors bind.Therefore, combine the ability of RUP3 acceptor to be directly connected to the binding affinity of test compounds and RUP3 acceptor with " radiolabeled The compounds of this invention " or the competition of radiolabeled RUP3 part.
Measure the verification scheme of RUP3 receptors bind
The preparation of ARUP3 acceptor
293 cell (human kidneys with human RUP3 acceptor of 10 μ g and the of short duration transfection of 60 μ L Lipofectamine (each 15-cm dish); ATCC) in dish under substratum replacing condition the growth 24 hours (75% degree of converging); And the Hepes-EDTA damping fluid (20mMHepes+10mMEDTA, pH value 74) with every dish 10mL shifts out.Then make cell in Beckman Coulter whizzer with 17, centrifugal 20 minutes of 000rpm (JA-25.50 rotor).Next make cell granule resuspending in the pH value is 74 20mMHepes+1mMEDTA, and it is homogenized and recentrifuge with the 50mLDounce clarifixator.After removing supernatant, the cell granule is stored in-80 ℃ up to combining check.When being used to check, film being thawed on ice 20 minutes and then be added into and cultivate damping fluid (20mM Hepes, 1mM MgCl
2, 100mM NaC1, pH value 74).Then stirring said film also homogenized 15 seconds unprocessed film granule resuspending at 6 grades with Brinkmann PT-3100Polytron clarifixator.Measure membrane protein concentration with the check of BRLBradford protein.
B. combine check
For total associativity, with TV be 50 μ L quilt suitably the film of dilution (be diluted in and contain 50mM Tris HCl (pH value 74), 10mMMgCl
2In the check damping fluid of 1mMEDTA; 5-50 μ g protein) add in the 96 hole Vestolen PP 7052 microtiter plates, add 100 μ L check damping fluid and the radiolabeled RUP3 part of 50 μ L then.For non-specific binding, before adding the radiolabeled RUP3 part of 50 μ L, add the check damping fluid of 50 μ L rather than 100 μ L and the cold RUP3 of 10 μ M of the other 50 μ L of interpolation.Then plate was at room temperature cultivated 60-120 minute.Through making inspection panel stop this association reaction having on the micro-pore plate type device GF/C Unifilter screen plate of Brandell 96 orifice plate scoops to filter, then clean with the cold Tris HC1 of 50mM (pH value 74) that contains 09%NaC1.Then,, in each hole, add 50 μ L Optiphase Supermix,, and plate is counted with Trilux MicroBeta scintillometer with the top seal of inspection panel with the screen plate bottom seals.In order to carry out the competitive research of compound, 100 μ L are added in the suitable hole through the test compounds rather than the 100 μ L check damping fluid of suitably dilution, then add the radiolabeled RUP3 part of 50 μ L.
C. calculate
Under 1 and 01 μ M concentration and then verification test compound under selected concentration range at first so that middle dosage can cause about 50% (be IC to radio-labeling RUP3 part bonded restraining effect
50).Specificity when not having test compounds combines (B
O) be total combination (B
T) deduct the difference of non-specific binding (NSB), and similarly, it is that displacement combines (displacement binding) (B (B) that specificity combines (having test compounds)
D) deduct the difference of non-specific binding (NSB).From the restraining effect response curve, measure IC
50, said restraining effect response curve is the decilog-logarithmic curve of B/Bo per-cent and test compounds concentration.
By Cheng and Prustoff transfer equation calculating K
1:
K
1＝IC
50/(1+[L]/K
D)
Wherein [L] is the concentration of used radio-labeling RUP3 part in the check, and K
DIt is the independent radio-labeling RUP3 part dissociation constant of measuring under the identical combination condition.
The chemical case of The compounds of this invention is synthetic
It is synthetic with it to further specify The compounds of this invention through following instance.It is to be limited in the details of these instances for further explain the present invention rather than with the present invention that following instance is provided.This paper, preceding text and compound hereinafter described are according to CS Chem Draw Ultra Version 701, and Auto Nom version2.2 names.In particular case, use popular name and should be appreciated that one of ordinary skill in the art will confirm said popular name.
Chemistry. through the Varian Mercury Vx-400 that is furnished with one four nuclear automatic conversion probe and z-gradient or the Bruker Avance-400 that is furnished with QNP (Quad nuclear probe) or BBI (oppositely popping one's head in the broadband) and z-gradient write down proton nuclear magnetic resonance (
1H NMR) spectrum.Chemical shift is that unit provides with PPM (ppm), uses the residual solvent signal to be reference.Use following NMR abbreviation: s=is unimodal, d=is bimodal, t=three peaks, q=four peaks, m=multimodal, br=broad peak.Use Smith's synthesizer (Smith Synthesizer) (Personal Chemistry) to carry out microwave irradiation.At silica gel 60F
254(Merck) carry out thin layer chromatography (TLC) on, on PK6F silica gel 60A 1mm plate (Whatman), prepare type thin layer chromatography (preparation type TLC), and at the enterprising administration-management column chromatography of Kieselgel 60 (Merck) silicagel column that uses 0 063-0 200mm.On the Buchi Rotary Evaporators, carry out vacuum-evaporation.Palladium using diatomaceous earth filtration process?
(Celite?
).
LCMS specification: 1) PC-HPLC-pump: LC-10AD VP, Shimadzu Inc; HPLC central controller: SCL-10AVP, Shimadzu Inc; UV-detector: SPD-10AVP, himadzu Inc; Self-actuated sampler: CTCHTS, PAL, Leap Scientific, mass spectrograph: Turbo is housed sprays ionogenic API 150EX, AB/MDS Sciex, software: Analyst 1 22) Mac.HPLC-pump: LC-8AVP, Shimadzu Inc; HPLC central controller: SCL-10AVP, Shimadzu Inc.
UV-detector: SPD-10A VP, Shimadzu Inc; Self-actuated sampler: 215 liquid processors, Gilson Inc, mass spectrograph: Turbo is housed sprays ionogenic API 150EX, AB/MDS Sciex software: Masschrom 152.
Instance 9
Instance 91 preparation 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-t-butyl formate (compd A 1).
Step 1: preparation 5-amino-1-(4-methylsulfonyl-phenyl)-1H-pyrazoles-4-nitrile.
Be furnished with reflux exchanger and N to one
2The inlet dividing plate round-bottomed flask (100mL) pack into 4-(methylsulfonyl) phenyl hydrazine hydrochloride (2g, 9mmol) and sodium methylate (0 49g, 9mmol).At room temperature in nitrogen gas stream, add methyl alcohol (20mL).Reaction mixture is stirred 15-20min to disappear and the generation white precipitate until purple.(11g, 9mmol) and at room temperature restir 10min then makes reaction mixture refluxed 150min then to add Ethoxy methylene malononitrile 99.The refrigerative reaction mixture is filtered and reduced-pressure backflow generation crude product.Solid residue is dissolved in EtOAc/H
2O.Collect the EtOAc layer, it is washed with saturated water-based NaCl, through NaSO
4Second part of crude product of dry and concentrated generation.Make crude product through flash chromatography purifying (10%CH
3OH/CH
2Cl
2) and produce the product (625mg, 26%) be yellow crystals from methanol crystallization.
1HNMR(DMSO-d
6，400MHz)δ3?27(s，3H)，6.98(s，2H)，7?81(d，2H)，7?88(s，1H)，8.06(s，2H)。LCMS C
11H
10N
4O
2S calculated value 262 05, observed value 262 9 (MH
+).
Step 2: preparation 1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-alcohol.
Under 102 ℃, make 5-amino-1-(4-methylsulfonyl-phenyl)-1H-pyrazoles-4-nitrile (540mg), formic acid (10mL) and 1mL H
2The mixture of O refluxes overnight.After being cooled to room temperature, observe white precipitate.Use H
2O (10mL) diluted mixture thing makes it filter and use H through funnel
2O, CH
3OH and diethyl ether thoroughly wash.Collect white solid and make its dry crude product (300mg, productive rate 50%) that produces under vacuum.
1H?NMR(DMSO-d
6，400MHz)δ3.26(s，3H)，8?12(d，2H)，829(s，1H)，8?42(d，2H)，8?44(d，1H)，12?61(s，1H)。LCMS.C
12H
10N
4O
3S calculated value 290 05, observed value 291 2 (MH
+).
Step 3: preparation 4-chloro-1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine.
To being furnished with reflux exchanger and N
2The 50mL round-bottomed flask of inlet dividing plate pack into stirring rod, 1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-alcohol (93mg, 0 32mmol), xylidine (03mL) and POCl
3(10mL).At room temperature at N
2In reaction mixture is stirred 5min and makes its backflow 6h.After being cooled to room temperature, reaction mixture is poured in the ice and used CH
2Cl
2Extraction fast.Then, obtain 24mg product (productive rate 27%) through flash chromatography (EtOAc. hexane=11) purifying crude product.
1HNMR(DMSO-d
6，400MHz)δ3?29(s，3H)，8?19(d，2H)，8.53(d，2H)，8?89(s，1H)，9?08(s，1H)。LCMS C
12H
9ClN
4O
2S calculated value 308.01, observed value 309 1 (MH
+).
Sodium hydride (7 8mg, 60%, 0 195mmol in the oil) and 0 5mLTHF pack in the 16mL reaction flask.In suspension-s, add 4-hydroxy-piperdine-1-t-butyl formate (10mg, 0 0487mmol) also at room temperature at N
2In mixture is stirred 20min, then slowly add 4-chloro-1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine (10mg, 0 0325mmol).At room temperature at N
2After the middle stirred overnight, LCMS shows that whole initial chloridization pyrazole pyrimidines transform fully.Then in a vacuum concentrated reaction mixture and through with 50%EtOAc/ alkane as the hurried tubing string chromatography of scrub solution with its purifying.
1H?NMR(CDCl
3，400MHz)δ1?49(s，9H)，1?85(m，2H)，2?09(m，2H)，3?10(s，3H)，3?32(m，2H)，3?86(m，2H)，5.60(m，1H)，8?09(d，2H)，8?26(s，1H)，8.61(d，2H)，8.66(s，1H)。LCMS C
22H
27N
5O
5S calculated value 473 17, observed value 474 4 (MH
+).
Instance 92 preparation 4-[1-(4-methylsulfonyl-phenyl)-3-methyl isophthalic acid H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-t-butyl formate (compd A 2).
According to the general process in the preceding text instance 91, obtain to be 5-amino-1-(4-methylsulfonyl-phenyl)-3-methyl isophthalic acid H-pyrazoles-4-nitrile of yellow solid with 1-oxyethyl group ethylidene propane dinitrile and 4-(methylsulfonyl) phenyl hydrazine hydrochloric acid.
1H?NMR(DMSC-d
6，400MHz)δ2.18(s，3H)，3?26(s，3H)，6?94(s，2H)，7?9(d，2H)，8?03(s，2H)。LCMS.C
12H
12N
4O
2S calculated value 276 07, observed value 277 1 (MH
+).
Step 2: preparation 1-(4-methylsulfonyl-phenyl)-3-methyl isophthalic acid H-pyrazolo [3,4-d] pyrimidine-4-alcohol.
According to instance 91 described general process, preparation also separates title compound 1-(4-methylsulfonyl-phenyl)-3-methyl isophthalic acid H-pyrazolo [3,4-d] pyrimidine-4-alcohol.
1HNMR(DMSO-d
6/CDCl
3，400MHz)δ2?54(s，3H)，3?13(s，3H)，8?02(d，2H)，8?05(s，1H)，8?42(d，2H)，12?41(s，1H)。LCMS C
13H
12N
4O
3S calculated value 304.06, observed value 305 1 (MH
+).
Step 3: preparation 4-chloro-1-(4-methylsulfonyl-phenyl)-3-methyl isophthalic acid H-pyrazolo [3,4-d] pyrimidine.
According to the general process of instance 91, separate title compound and through hurried tubing string chromatography with its purifying.
1HNMR(CDCl
3，400MHz)δ2?84(s，3H)，3?011(s，3H)，8?11(d，2H)，8?60(d，2H)，8.87(s，1H)。LCMS C
14H
13ClN
4O
2S calculated value 336 04, observed value 3372 (MH
+).
Step 4: preparation 4-[1-(4-methylsulfonyl-phenyl)-3-methyl isophthalic acid H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-t-butyl formate (compd A 2).
General process through instance 91 prepares compd A 2.
1H?NMR(CDCl
3，400MHz)δ1?49(s，9H)，1?89(m，2H)，2?07(m，2H)，2?70(s，3H)，3?09(s，3H)，3?49(m，2H)，3?88(m，2H)，5?62(m，1H)，8?08(d，2H)，8?58(s，2H)，8?61(s，1H)。LCMS C
23H
29N
5O
5S calculated value 487 19, observed value 488 4 (MH
+).
Instance 93. preparation 4-[1-(4-methylsulfonyl-phenyl)-3,6-dimethyl--1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-t-butyl formate (compound A-13).
To being furnished with reflux exchanger and N
250mL round-bottomed flask pack into stirring rod, 5-amino-1-(4-methylsulfonyl-phenyl)-3-methyl isophthalic acid H-pyrazoles-4-nitrile (85mg, 0 31mmol) and the Acetyl Chloride 98Min. (5mL) of inlet dividing plate.Under 60 ℃ at N
2In reaction mixture is stirred 24h.Decompression removes Acetyl Chloride 98Min. and uses CH
2Cl
2With EtOA wash solids resistates and through filtering with its collection.Then through flash chromatography (EtOAc hexane=1 1) purifying crude product and make its crystallization from methyl alcohol.Obtain 55mg product (productive rate 56%).
1H?NMR(DMSO-d
6，400MHz)δ2?07(s，3H)，2?36(s，3H)，3.29(s，3H)，7?81(d，2H)，8?09(d，2H)，10?7(s，1H)。LCMS.C
14H
14N
4O
3S calculated value 318 08, observed value 319.1 (MH
+).
Add N-[4-cyanic acid-2-(4-methylsulfonyl-phenyl)-5-methyl-2H-pyrazole-3-yl]-ethanamide (30mg, 0 079mmol), H to the 50mL round-bottomed flask of being furnished with stirring rod and reflux exchanger
2O (0 6mL) and ethanol (1mL) then add 20% water-based KOH (0 33mL).Reaction mixture becomes purple and solid dissolving after adding KOH.Then in above-mentioned solution, add hydrogen peroxide (0 25mL).After at room temperature stirring 15min, heating is overnight down at 75 ℃ with reaction mixture.After being cooled to room temperature, slowly add acetate reaches 6-65 until the pH value scope.Then use H
2O and methyl alcohol diluted mixture thing.Collect the gained deposition and use H through filtering
2O, methyl alcohol, diethyl ether washing and dried in vacuum.Crude product directly is used for next step without other purifying.
1H?NMR(DMSO-d
6，400MHz)δ1?71(s，2H)，2?39(s，3H)，2?51(s，1H)，3?25(s，3H)，8?05(d，2H)，8.46(d，2H)。LCMS C
14H
14N
4O
3S calculated value 318 08, observed value 319.1 (MH
+).
Step 3: preparation 4-chloro-1-(4-methylsulfonyl-phenyl)-3,6-dimethyl--1H-pyrazolo [3,4-d] pyrimidine.
According to the general process of instance 91, separate title compound and through hurried tubing string chromatography with its purifying.
1H?NMR(CDCl
3，400MHz)δ2.79(s，3H)，2?86(s，3H)，3?09(s，3H)，8?10(d，2H)，8.61(d，2H)。LCMSC
14H
13ClN
4O
2S calculated value 336 04, observed value 337 2 (MH
+).
Step 4: preparation 4-[1-(4-methylsulfonyl-phenyl)-3,6-dimethyl--1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-t-butyl formate (compound A-13).
General process through instance 91 prepares compound A-13.
1HNMR(CDCl
3，400MHz)δ1.49(s，9H)，1?89(m，2H)，2?07(m，2H)，2?66(s，3H)，2?70(s，3H)，3?08(s，3H)，3?49(m，2H)，3?68(m，2H)，5?65(m，1H)，8?05(d，2H)，8.59(d，2H)。LCMS C
24H
31N
5O
5S calculated value 5012, observed value 5024 (MH
+).
Instance 94 preparation 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-tetryl formate (compd A 4).
The general process that carbamate forms
At room temperature with compd A 6 among the DMF (8mL) (150mg, 0.367mmol), the mixture stirring 1h of isobutyl chlorocarbonate (0 057mL, 0 44mmol) and triethylamine (0 1mL).Add entry and collecting precipitation to mixture.Acquisition is solid compd A 4 (88%).
1HNMR(CDCl
3，400MHz)δ0?95(d，6H)，1?86-1?98(m，3H)，211-213(m，2H)，3?10(s，3H)，3?37-3?43(m，2H)，3?89-3?95(m，4H)，5?64-5?68(m，1H)，8?09-8?12(m，2H)，8.26(s，1H)，8?60-8?63(m，2H)，8?67(s，1H)。C
22H
27N
5O
5The accurate mass calculated value 473 2 of S, experimental value 474 3 (MH
+).
Instance 95: preparation 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-tetryl formate (compound A-45).
Obtain to be solid compound A-45 (95%) through instance 94 described general process.
1H NMR (CDCl
3, 400MHz) δ 1 26 (d, 6H), 1 82-1 86 (m, 2H), 2 01-2 10 (m, 2H); 3 10 (s, 3H), 3.34-3 45 (m, 2H), 3 90-3 93 (m, 2H); 4 94 (nine heavy peaks, 1H), 5 44-5 48 (m, 1H), 8 09-8 12 (m, 2H); 8 26 (s, 1H), 8 60-8 62 (m, 2H), 8 67 (s, 1H).C
21H
25N
5O
5The accurate mass calculated value 459.2 of S, experimental value 460 3 (MH
+).
Instance 96: preparation 1-(4-methylsulfonyl-phenyl)-4-(piperidin-4-yl oxygen base)-1H-pyrazolo [3,4-d] pyrimidine (compd A 6).
Generally go protection method
In the 200mL round-bottomed flask, pack into stirring rod, compd A 1 (12g), anhydrous acetonitrile (50mL) and methylene dichloride (15mL).Under nitrogen, add 1, the 4MHCl in the 4-diox (15mL) also stirs 10min with mixture under 40 ℃.The muddiness of solution becomes.Produce compd A 6 with precipitate and separate and through the HPLC purifying.
1H?NMR(DMSO-d
6，400MHz)δ2?04(m，2H)，2?25(m，2H)，3.21(m，2H)，328(s，3H)，3.32(m，2H)，5?60(m，1H)，8?16(d，2H)，?8?61(d，2H)，8?70(s，1H)，8.79(s，1H)。LCMSC
17H
19N
5O
3S calculated value 373.12, observed value 3741 (MH
+).
Instance 97: preparation { 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [34-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-pyridin-3-yl-ketone (compd A 7).
The general forming method of acid amides
In the 500mL round-bottomed flask, pack into compd A 6 (146mg, 0 36mmol) and triethylamine (300 μ l).Add DMF (15mL) with complete dissolved solids material.(96mg 0.54mmol) adds solution also at room temperature at N with the nicotinoyl chlorine hydrochloride
2Down with the mixture stirred overnight.After LCMS showed that all initial amine transform fully, water was ended said reaction.Then reaction mixture is concentrated in a vacuum and purifying generation compd A 7 in preparation HPLC.
1H?NMR(CDCl
3，400MHz)δ206(m，2H)，2?22(m，2H)，3?09(s，3H)，3?55(m，1H)，3.79(m，2H)，4?15(m，1H)，5.76(m，1H)，7.86(m，1H)，8.11(d，2H)，8.28(s1H)，8.33(d，1H)，8.61(d，2H)，8.68(s，1H)，8?84(m，1H)，8?92(m，1H)。LCMS C
23H
22N
6O
4S calculated value 478 14, observed value 479 1 (MH
+).
Instance 98: preparation 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-butyl formate (compd A 48).
With 1-(4-methylsulfonyl-phenyl)-4-(piperidin-4-yl oxygen base)-1H-pyrazolo [3; 4-d] pyrimidine hydrochloride (0 17mmol; 60mg), butyl chloroformate (0 19mmol, 24 μ L) and triethylamine (0 51mmol, 71 μ L) are dissolved among the DMF (2mL) and at room temperature it are stirred 60min.The reaction mixture water is ended then to use ethyl acetate extraction.Remove organic solvent in the vacuum and produce the solid compd A 48 (40mg, 50%) that is white in color.
1H?NMR(400MHz，CDCl
3)δ(ppm)8.67(s，1H)，8?62(d，2H)，8.26(s，1H)，8?11(d，2H)，5?62(h，1H)，4?12(t，2H)，3?92(m，2H)，3?39(m，2H)，3?10(s，3H)，2?11(m，2H)，1?65(m，2H)，1?56(p，2H)，1?42(s，2H)，0?97(t，3H)。C
22H
27N
5O
5The accurate mass calculated value 473 55 of S, experimental value 474 4 (MH
+).
Instance 9.9: preparation 4-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base sulfenyl]-piperidines-1-formic acid ring third methyl esters (compd A 112).
With diimidazole-1-base-ketone (0 25mmol, 41mg) and cyclopropyl-carbinol (0 25mmol, 20 μ L) is dissolved among the DMSO (2mL) and at room temperature it is stirred 30min.Then add 1-(2-fluoro-4-methylsulfonyl-phenyl)-4-(piperidin-4-yl sulfenyl)-1H-pyrazolo [3,4-d] pyrimidine hydrochloride (0 18mmol, 80mg) and triethylamine (0 54mmol, 75 μ L).Under 120 ℃ in microwave with mixture heating up 5min.Monitor said reaction by thin layer chromatography and LCMS.Produce the solid compd A 112 (26mg, 29%) that is white in color through the HPLC purifying.
1HNMR(400MHz，CDCl
3)δ(ppm)8?72(s，1H)，8?41(s，1H)；7?87(m，3H)；4.40(h，1H)；4.01(m，2H)，3?87(d，2H)，3?19(m，2H)，3?06(s，3H)，2?17(m，2H)，1?73(m，2H)，1?07(m，1H)，0?51(m，2H)，0?25(m，2H)。C
22H
24FN
5O
4S
2Accurate mass calculated value 505 59, experimental value 506 20 (MH
+).
Instance 910. preparation 4-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base sulfenyl]-piperidines-1-formic acid ring fourth methyl esters (compd A 113).
With diimidazole-1-base-ketone (0.25mmol, 41mg) and cyclobutanemethanol (0 25mmol, 24 μ L) is dissolved among the DMSO (2mL) and at room temperature it is stirred 30min.Then add 1-(2-fluoro-4-methylsulfonyl-phenyl)-4-(piperidin-4-yl sulfenyl)-1H-pyrazolo [3,4-d] pyrimidine hydrochloride (0 18mmol, 80mg) and triethylamine (0 54mmol, 75 μ L).Under 120 ℃, mixture is heated 5min in microwave.Monitor said reaction by thin layer chromatography and LCMS.Produce the solid compd A 113 (29mg, 31%) that is white in color through the HPLC purifying.
1HNMR(400MHz，CDCl
3)δ(ppm)8?71(s，1H)，8?22(s，1H)，7.87(m，3H)；4.37(h，1H)；4?00(m，4H)，3?16(m，2H)，3?05(s，3H)，2?56(m，1H)，2.12(m，2H)，2?01(m，2H)，1?85(m，2H)，1?73(m，4H)。C
23H
26FN
5O
4S
2Accurate mass calculated value 519 61, experimental value 520.3 (MH
+).
Instance 911: preparation 4-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base sulfenyl]-piperidines-1-formic acid 2-cyclopropyl-ethyl ester (compd A 114).
(0 25mmol 41mg) is dissolved among the DMSO (2mL) also at room temperature with its stirring 30min with 2-cyclopropyl-ethanol (0 25mmol, 32 μ L) with diimidazole-1-base-ketone.Then add 1-(2-fluoro-4-methylsulfonyl-phenyl)-4-(piperidin-4-yl sulfenyl)-1H-pyrazolo [3,4-d] pyrimidine hydrochloride (0 18mmol, 80mg) and triethylamine (0 54mmol, 75 μ L).Under 120 ℃, mixture is heated 5min in microwave.Monitor said reaction by thin layer chromatography and LCMS.Produce the solid compd A 114 (35mg, 36%) that is white in color through the HPLC purifying.
1HNMR (400MHz, CDCl
3) δ (ppm) 8 71 (s, 1H), 8 21 (s, 1H); 7.86 (m, 3H); 4 37 (m, 1H), 4 10 (t, 2H), 3 96 (single broad peak, 2H), 3 19 (m, 2H); 3 04 (s, 3H), 2 12 (m, 2H), 1 72 (m, 2H), 1 48 (m, 2H), 1 39 (m, 2H), 1 00 (m, 2H), 0 65 (m, 1H).C
23H
26FN
5O
4S
2Accurate mass calculated value 519.61, experimental value 520.3 (MH
+).
Instance 912: preparation (5-bromo-furans-2-yl)-{ 4-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base sulfenyl]-piperidines-1-yl }-ketone (compd A 115).
With oxalyl chloride (0 51mmol, 45 μ L) and DMF (catalytic amount) add 5-bromo-furans-2-formic acid in the methylene dichloride (3mL) (0 18mmol, 36mg).At room temperature reaction mixture is stirred 40min.Remove organic solvent in a vacuum.Enriched material is dissolved in the methylene dichloride again and adds 1-(2-fluoro-4-methylsulfonyl-phenyl)-4-(piperidin-4-yl sulfenyl)-1H-pyrazolo [3; 4-d] pyrimidine hydrochloride (0 16mmol; 70mg) and triethylamine (0 47mmol, 66 μ L) and at room temperature it is stirred 15h.Monitor said reaction process by thin layer chromatography and LCMS.Produce the solid compd A 115 (45mg, 41%) that is white in color through the HPLC purifying.
1HNMR (400MHz, CDCl
3) δ (ppm) 8 74 (s, 1H), 8 25 (s, 1H), 7 87 (m, 3H), 7 00 (d, 1H), 6 49 (s, 1H), 4 50 (h, 1H), 4 34 (m, 2H), 3 42 (single broad peak, 2H), 2 70 (s, 3H), 2 28 (m, 2H), 1 85 (m, 2H).C
22H
19BrFN
5O
4S
2Accurate mass calculated value 580 45, experimental value 582 3 (MH
+).
Instance 913: preparation 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-pentyl formate (compd A 117).
With diimidazole-1-base-ketone (0 51mmol, 83mg) and Pentyl alcohol (0 51mmol, 56 μ L) is dissolved among the DMSO (1mL) and at room temperature it is stirred 30min.Then, add 1-(4-methylsulfonyl-phenyl)-4-(piperidin-4-yl oxygen base)-1H-pyrazolo [3,4-d] pyrimidine (0 17mmol, 70mg) and triethylamine (0 51mmol, 72 μ L) and under 120 ℃, in microwave, heat 6min.Through LCMS monitoring reaction process.The ethyl acetate extraction product is ended and used to the reaction mixture water.Remove organic solvent in the vacuum and produce the solid compd A l17 (33mg, 32%) that is white in color through the HPLC purifying.C
23H
29N
5O
5The accurate mass calculated value 487 57 of S, experimental value 488 20 (MH
+).
Instance 914: preparation 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-formic acid 1-ethyl-propyl ester (compd A 118).
(0 51mmol 83mg) is dissolved among the DMSO (1mL) also at room temperature with its stirring 30min with penta-3-alcohol (0 51mmol, 56 μ L) with diimidazole-1-base-ketone.Then, add 1-(4-methylsulfonyl-phenyl)-4-(piperidin-4-yl oxygen base)-1H-pyrazolo [3,4-d] pyrimidine (0.17mmol, 70mg) and triethylamine (0 51mmol, 7 μ L2) and under 120 ℃, in microwave, heat 6min.Through LCMS monitoring reaction process.The ethyl acetate extraction product is ended and used to the reaction mixture water.Remove organic solvent in the vacuum and produce the solid compd A 118 (14mg, 14%) that is white in color through the HPLC purifying.C
23H
29N
5O
5The accurate mass calculated value 487 57 of S, experimental value 488 20 (MH
+).
Instance 915: preparation 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-formic acid 2-ethyl-butyl ester (compd A 119).
(0 51mmol, 83mg) (0 51mmol 52mg) is dissolved among the DMSO (1mL) also at room temperature with its stirring 30min with 2-ethyl-Ding-1-alcohol with diimidazole-1-base-ketone.Then, add 1-(4-methylsulfonyl-phenyl)-4-(piperidin-4-yl oxygen base)-1H-pyrazolo [3,4-d] pyrimidine (0 17mmol, 70mg) and triethylamine (0 51mmol, 72 μ L) and under 120 ℃, in microwave, heat 6min.Through LCMS monitoring reaction process.The ethyl acetate extraction product is ended and used to the reaction mixture water.Remove organic solvent in the vacuum and produce the solid compd A 119 (38mg, 36%) that is white in color through the HPLC purifying.C
24H
31N
2O
5The accurate mass calculated value 50160 of S, experimental value 5023 (MH
+).
Instance 916: preparation 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-formic acid ring penta methyl esters (compd A 120).
With diimidazole-1-base-ketone (0 51mmol, 83mg) and cyclopentyl-methyl alcohol (0 51mmol 51mg) is dissolved among the DMSO (1mL) and at room temperature it is stirred 30min.Then, add 1-(4-methylsulfonyl-phenyl)-4-(piperidin-4-yl oxygen base)-1H-pyrazolo [3,4-d] pyrimidine (0 17mmol, 70mg) and triethylamine (0 51mmol, 72 μ L) and under 120 ℃, in microwave, heat 6min.Through LCMS monitoring reaction process.The ethyl acetate extraction product is ended and used to the reaction mixture water.Remove organic solvent in the vacuum and produce the solid compd A 120 (30mg, 29%) that is white in color through the HPLC purifying.C
24H
29N
5O
5The accurate mass calculated value 499 58 of S, experimental value 500 4 (MH
+).
Instance 917: preparation 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-formic acid 2,2-dimethyl--propyl ester (compd A 124).
With 1-(4-methylsulfonyl-phenyl)-4-(piperidin-4-yl oxygen base)-1H-pyrazolo [3; 4-d] pyrimidine hydrochloride (0 17mmol; 70mg), chloroformic acid peopentyl ester (0.25mmol, 37 μ L) and triethylamine (0.51mmol, 72 μ L) are dissolved among the DMF (2mL) and at room temperature it are stirred 60min.Monitor the process of said reaction by TLC and LCMS.Water stopped reaction mixture.Use the ethyl acetate extraction product.Remove organic solvent in the vacuum and produce the solid compd A 124 (28mg, 27%) that is white in color through the HPLC purifying.C
23H
29N
5O
5The accurate mass calculated value 487 57 of S, experimental value 488 20 (MH
+).
Instance 918: preparation (5-butyl-pyridine-2-yl)-{ 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone (compd A 125).
With 5-butyl-pyridine-2-formic acid (92mg, 0.51mmol) and isopropyl chlorocarbonate (70 μ L, 0 51mmol) be dissolved among the DMF and at room temperature stir 40min.(72 μ L 0.51mmol) also continue to stir 24h then to add 1-(4-methylsulfonyl-phenyl)-4-(piperidin-4-yl oxygen base)-1H-pyrazolo [3,4-d] pyrimidine hydrochloride (70mg, 0 17mmol) and triethylamine.Monitor the process of said reaction by TLC and LCMS.Remove organic solvent in the vacuum and produce the solid compd A 125 (13mg, 13%) that is white in color through the HPLC purifying.C
27H
30N
6O
4The accurate mass calculated value 534 63 of S, experimental value 535 20 (MH
+).
Instance 9.19: preparation (4-difluoro-methoxy-phenyl)-{ 4-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone (compd A 193).
At room temperature (527mg is 28mmol) with HATU (106g, 28mmol) common stirring 30min in DMF with the acid of 4-difluoro-methoxy-benzyl.Then add 1-(2-fluoro-4-methylsulfonyl-phenyl)-4-(piperidin-4-yl oxygen base)-1H-pyrazolo [3,4-d] pyrimidine hydrochloride (800mg, 1.87mmol) and triethylamine (785 μ L, 5 61mmol).The gained mixture is stirred 24h.Monitor the process of said reaction by TLC and LCMS.Remove organic solvent in the vacuum and produce the compd A 193 (127mg, 32%) be beige solid through the HPLC purifying.C
25H
22F
2N
5O
5The accurate mass calculated value 561 53 of S, experimental value 562.2 (MH
+).
Instance 920: preparation 1-(2-fluoro-4-methylsulfonyl-phenyl)-4-[1-(the 3-sec.-propyl-[1,2,4] oxadiazole-5-yls)-piperidin-4-yl oxygen base]-1H-pyrazolo [3,4-d] pyrimidine (compd A 198).
Step 1: preparation N-hydroxyl-NSC 18620.
With the isopropyl cyanide among the EtOH (20L) (276g, 40mol) solution and azanol (50% aqueous solution, 1 1L, 16mol) chemical combination and make its backflow 5h.Then remove solvent in a vacuum and in toluene azeotropic remove residual water.Resistates is dissolved in CH
2Cl
2, make it through MgSO
4Drying, and solvent removal produced white solid (402g, productive rate 98%).
1HNMR(CDCl
3)δ7?94(br?s，1H)，4?55(br?s，2H)，2?47(m，1H)，1?20(d，6H，J＝7?1Hz)。
Step 2: preparation 1-cyanic acid-4-hydroxy piperidine.
With 5L, 3 mouthfuls of flask make-up machinery stirrers, reflux exchanger and powder feed hoppers.(840g 10mmol), then progressively adds entry (about 300-400mL) when vigorous stirring forms thick, homogeneous slurries to add sodium hydrogencarbonate while stirring through the powder feed hopper.Then flask is placed ice bath, then add CH
2Cl
24-hydroxy piperidine (10L) (506g, 500mol) solution, and the content vigorous stirring cooled off.Dropwise add CH through 2h
2Cl
2Cyanogen bromide (600mL) (640g, 6 0mol) solution, and continue to stir 30min again.Remove ice bath, replace mechanical stirrer, and reaction mixture is stirred 16h with magnetic stirrer.Flask is placed under the mechanical stirrer once more, and adding yellow soda ash (100g) is guaranteed to neutralize fully.Add MgSO
4(500g) and continue vigorous stirring 15min.Filter gained suspension-s and use CH
2Cl
2(20L) flushing.When solvent removal, obtain the light amber toughening oil, produce 1-cyanic acid-4-hydroxy piperidine (574g, productive rate 91%).
1HNMR(CDCl
3)δ3?80(m，1H)，3?39(m，2H)，3?05(m，2H)，1?87(m，2H)，1?70(br?s，1H)，1?62(m，2H)，MSm/z?2121(M
+)。
Step 3: preparation 1-(the 3-sec.-propyl-[1,2,4] oxadiazole-5-yls)-piperidines-4-alcohol.
In the variant of the said method of people such as Yarovenko (Bull.Acad Sci USSR, Div Chem Sci 1991,40,1924), last 15min with ZnCl
2((12 2g, 120mmol) (12 6g are 100mmol) in the solution with 4-hydroxy-piperdine-1-nitrile 120mmol) dropwise to add N-hydroxyl-NSC 18620 in the ETHYLE ACETATE (500mL) of vigorous stirring for 1N in the ether, 120mL.Form deposition when reinforced rapidly, and stirring rod is fixed in the matrix on one point, it is reinforced to need the hand shaken reactant to continue residue.Behind the static 15min, pour out supernatant liquid and filtration, resistates with ether flushing twice, is formed white precipitate, collect said deposition through filtering.Said material dissolves in dense HCl (50mL), is diluted to 4N and the 1h that refluxes with EtOH (100mL).During cooling, remove white precipitate, then filtrating is reduced to 50mL and also dilutes with 100mL water through filtration.Add solid Na
2CO
3Until mixture is alkalescence, adds CH
2Cl
2, and, use CH with the filtration of gained mixture
2Cl
2Flushing.Separate organic extract, through MgSO
4Drying, and solvent removal produced the 1-be thick, amber oil (3-sec.-propyl-[1,2,4] oxadiazole-5-yls)-piperidines-4-pure (150g, productive rate 71%):
1HNMR (CDCl
3) δ 395 (m, 3H), 337 (m, 2H), 2.88 (m, 1H), 2 34 (br s, 1H), 1 93 (m, 2H), 1 63 (m, 2H), 1 28 (d, 6H, J=71Hz), MSm/z 212 3 (M
+).
Step 4: preparation 1-(2-fluoro-4-methylsulfonyl-phenyl)-4-[1-(the 3-sec.-propyl-[1,2,4] oxadiazole-5-yls)-piperidin-4-yl oxygen base]-1H-pyrazolo [3,4-d] pyrimidine (compd A 198).
At room temperature (338mg is 16mmol) with sodium hydride (87mg, 366mmol) common stirring 30min in anhydrous THF (2mL) with 1-(3-sec.-propyl-[1,2,4] oxadiazole-5-yls)-piperidines-4-alcohol.Then add 4-chloro-1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] Mi Dingbing and at room temperature reactant is continued to stir 45min.Monitor said process by thin layer chromatography and LCMS.The water stopped reaction is also wanted compound with ethyl acetate extraction.The organic molten layer of evaporation in the vacuum.Produce the solid that is white in color through the HPLC purifying and want compd A 198 (600mg, 98%).C
22H
24FN
7O
4The accurate mass calculated value 501 53 of S, experimental value 502 2 (MH
+).
Instance 921 preparation 2-{4-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-1-(4-trifluoromethoxy-phenyl)-ethyl ketone (compd A 94).
General alkylation process
To being furnished with N
2Stirring rod, 1-(2-fluoro-4-methylsulfonyl-phenyl)-4-(piperidin-4-yl oxygen base)-1H-pyrazolo [3,4-d] pyrimidine (43mg, 0 1mmol), K pack in the 10mL round-bottomed flask of inlet
2CO
3(138mg, 1mmol) and DMF (1mL).Add a 2-bromo-1-(4-trifluoromethoxy-phenyl)-ethyl ketone (30mg, 0 1mmol).At room temperature reaction mixture is stirred 30min.Filter gained suspension-s and it is concentrated under vacuum.Produce compd A 94 through the thick resistates of preparation HPLC purifying.
1HNMR(CDCl
3，400MHz)δ2?43(m，2H)，2?59(m，2H)，314(s，3H)，368(m，2H)，378(m，2H)，478(s，2H)，581(m，1H)，735(d，2H)，7.96(m，3H)，8?01(m，2H)，8?42(s，1H)，8.65(s，1H)。C
26H
23F
4N
5O
5The accurate mass calculated value 593 14 of S, experimental value 594 3 (MH
+).
Instance 922: preparation 2-{4-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-1-(3-fluoro-phenyl)-ethyl ketone (compd A 95).
To be similar to instance 921 described modes, prepare compd A 95 through the preparation HPLC purifying.
1HNMR(CDCl
3，400MHz)δ2?43(m，2H)，2?59(m，2H)，3?14(s，3H)，3?73(m，4H)，4?78(s，2H)，5.81(m，1H)，7.37(m，1H)，7?51(m，1H)，7?63(m，1H)，7?71(m，1H)，7?96(m，3H)，8.01(m，2H)，8?41(s，1H)，8?65(s，1H)。C
25H
23F
2N
5O
4The accurate mass calculated value 527 14 of S, experimental value 5283 (MH
+).
Instance 923: preparation 2-{4-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-1-pyridine-2-base-ethyl ketone (compd A 96).
To be similar to instance 921 described modes, prepare compd A 96 through the preparation HPLC purifying.
1H?NMR(CDCl
3，400MHz)δ2?46(m，2H)，2?53(m，2H)，3?14(s，3H)，3?60(m，2H)，3?80(m，2H)，4?99(s，2H)，5?86(m，1H)，7?61(m，1H)，7?91(m，1H)，7.96(m，3H)，8?11(m，1H)，8?40(s，1H)，8?65(s，1H)，8?68(m，1H)。C
24H
23FN
6O
4The accurate mass calculated value 510 15 of S, experimental value 511 3 (MH
+).
Instance 924: preparation 4-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3; 4-d] pyrimidine-4-base oxygen base]-piperidines-1-t-butyl formate (compd A 74) and 4-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-isopropyl formate (compd A 129).
Step 1: preparation 5-amino-1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazoles-4-nitrile.
At room temperature at N
2In (2-fluoro-4-methylsulfonyl-phenyl)-hydrazine (1g, 4 89mmol) and sodium methylate (30mg, 0 489mmol) are dissolved in the methyl alcohol.Reaction mixture is stirred 10min and adds 2-oxyethyl group methylene radical-propane dinitrile (0 6g, 4 91mmol).Reaction mixture is stirred 30min and then makes its backflow 2h.Decompression removes solvent and resistates is suspended in water and uses ethyl acetate extraction.Water, brine wash organic layer also make it through dried over sodium sulfate.Concentrated solvent produces 5-amino-1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazoles-4-nitrile (1.2g, 87 5%) that is yellow solid.
1H?NMR(400MHz?DMSO-d
6)δ(ppm)7?96(d，1H)，7?93(m，1H)，7?80(s，1H)，7.74(m，1H)，6?89(s，2H)，3?24(s，3H)。C
11H
9FN
4O
2The accurate mass calculated value 280.04 of S, experimental value 281 30 (MH
+, 100%).
Step 2: preparation 1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-alcohol.
5-amino-1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazoles-4-nitrile (12g, 4 28mmol) is suspended in formic acid, and (20mL is 530mmol) and in the water (2mL) and make mixture backflow 18h.Make the reaction mixture cooling and add 15mL water, cause the solid 1-that is white in color (2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-alcohol (0 774g, 58.6%) deposition.Through filtered and recycled solid and water, methyl alcohol and ether thoroughly with its washing.It is overnight that powder is preserved under high vacuum.
1HNMR(400)MHz?DMSO-d
6)δ(ppm)：12?4(5，1H)，8?29(s，1H)，8.00(d，1H)，7?97(m，1H)，7?82(m，2H)，321(s，3H)。C
12H
9FN
4O
3The accurate mass calculated value 308 04 of S, experimental value 309 30 (MH
+, 100%).
Step 3: preparation 4-chloro-1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine.
1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-alcohol (0 774g, 2 51mmol) is suspended in POCl
3(23mL is 251mmol) and in the xylidine (0 69mL) and make mixture backflow 18h.Make the solvent concentrating under reduced pressure and resistates is loaded in the silicagel column.With 5% ethyl acetate/dichloromethane elution product.Remove solvent and produce solid 4-chloro-1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3, the 4-d] pyrimidine (0 781g, 95%) that is white in color.
1H?NMR(400MHzDMSO-d
d)δ(ppm)：9?14(s，1H)，9?07(s，1H)，8?34(d，1H)，8?24(m，1H)，8.20(m，1H)，3?55(s，3H)。C
12H
8ClFN
4The accurate mass calculated value 326 of S, experimental value 327 2 (MH
+100%).
Step 4: preparation 4-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-t-butyl formate (compd A 74).
Is being furnished with N
2The stirring rod, NaH of packing in the 500mL round-bottomed flask of inlet dividing plate (in the MO 60%, 18g, 45 6mmol) and 4-hydroxy-piperdine-1-t-butyl formate (153g, 7.6mmol).With THF (anhydrous, 80mL) add in the mixture.At room temperature with gained suspension-s stir about 30min.Then add a 4-chloro-1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine (2.5g, 7.6mmol).At room temperature at N
2Down with mixture stirred overnight and gained slurries little band yellow that becomes.With CH
2Cl
2Add in the slurries and filtration.Make filtrating concentrate and produce crude product in a vacuum.Use the tubing string purification by chromatography generation of 50%EtOAc/ hexane to be beige solid compd A 74.C
22H
26FN
5O
5The accurate mass calculated value 491 16 of S, experimental value 492 1 (MH
+).
Step 5: preparation 1-(2-fluoro-4-methylsulfonyl-phenyl)-4-(piperidin-4-yl oxygen base)-1H-pyrazolo [3,4-d] pyrimidine (compd A 238).
In the 500mL round-bottomed flask, pack into stirring rod, compd A 74 (400g), acetonitrile (80mL) and methylene dichloride (24mL).Under nitrogen, add 1, the 4M HCl in the 4-diox (24mL) also at room temperature stirs 20min with mixture.The muddiness of solution becomes.With precipitate and separate and make its dried in vacuum produce 1-(2-fluoro-4-methylsulfonyl-phenyl)-4-(piperidin-4-yl oxygen base)-1H-pyrazolo [3,4-d] pyrimidine.C
17H
18FN
5O
3The accurate mass calculated value 391 11 of S, experimental value 392 1 (MH
+).
Step 6: preparation 4-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-isopropyl formate (compd A 129).
In the 50mL round-bottomed flask, pack into 1-(2-fluoro-4-methylsulfonyl-phenyl)-4-(piperidin-4-yl oxygen base)-1H-pyrazolo [3,4-d] pyrimidine (80mg, 0 2mmol) and triethylamine (200 μ l).Add DMF (3mL) with complete dissolved solids material.Reaction flask is immersed in the ice bath.
With isopropyl chlorocarbonate (10M in the toluene, 0 22mL) add in the solution and under 0 ℃ at N
2In mixture is stirred 2h.After transforming fully through all initial amine of LCMS indication, end to finish reaction through water.Then reaction mixture is concentrated in a vacuum and pass through the preparation HPLC purifying and produce 4-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [34-d] pyrimidine-4-base oxygen base]-piperidines-1-isopropyl formate (compd A 129).
1HNMR(CDCl
3，400MHz)δ127(d，6H)，1?9(m，2H)，2?12(m，2H)，3?13(s，3H)，3.40(m，2H)，3?91(m，2H)，4?97(m，1H)，5?63(m，1H)，7.95(m，3H)，8?34(s，1H)，8?63(s，1H)。C
21H
24FN
3O
5The accurate mass calculated value 477 15 of S, experimental value 478.2 (MH
+).
Instance 9 25: preparation (4-ethyl-pyridine-2-yl)-{ 4-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone (compd A 135).
The general process of preparation acid amides
Is being furnished with N
2Stirring rod, 4-ethyl-pyridine-2-formic acid, phosphofluoric acid O-(7-azepine benzo triazol-1-yl)-N, N, N ', N '-tetramethyl-urea (180mg) and DMF (15mL) pack in the 50mL reaction flask of inlet.At room temperature at N
2Down mixture is stirred 20min.Add 1-(2-fluoro-4-methylsulfonyl-phenyl)-4-(piperidin-4-yl oxygen base)-1H-pyrazolo [3,4-d] pyrimidines (310mg) and triethylamine (403 μ l).At room temperature at N
2Under stir and make behind the 3-8h reaction mixture pass through injection filter to filter.To filtrate to concentrate and produce crude compound A135.Crude product is further purified through preparation HPLC.
1H?NMR(CDCl
3，400MHz)δ1?35(s，3H)，2?04(m，1H)，2.13(m，2H)，2?25(m，1H)，2?88(m，2H)，3?13(s，3H)，3?45(m，1H)，3?71(m，3H)，3?87(m，1H)，4?12(m，1H)，5?76(m，1H)，7?60(d，1H)，7?64(s，1H)，7.95(m，1H)，8?35(s，1H)，8?63(s，1H)，8?73(d，1H)。C
25H
25FN
6O
4The accurate mass calculated value 524 16 of S, experimental value 525 2 (MH
+).
Instance 926: preparation (5-bromo-pyridin-3-yl)-{ 4-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone (compd A 139).
To be similar to instance 925 described modes, prepare compd A 139 through the preparation HPLC purifying.C
23H
20BrFN
6O
4The accurate mass calculated value 574 04 of S, experimental value 575 2 (MH
+).
Instance 927: preparation (5-ethyl-pyridine-2-yl)-{ 4-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone (compd A 183).
To be similar to instance 925 described modes, prepare compd A 183 through the preparation HPLC purifying.
1H?NMR?(CDCl
3，400MHz)δ1?37(t，3H)，2.02(m，1H)，2.15(m，2H)，2?26(m，1H)，2?87(m，2H)，3?14(s，3H)，3?45(m，1H)，3?71(m，1H)，3?87(m，1H)，4?13(m，1H)，5?76(m，1H)，7?75(d，1H)，7?94(m，3H)，8?06(m，1H)，8?36(s，1H)，8?65(s，1H)，8?72(s，1H)。C
25H
25FN
6O
4The accurate mass calculated value 524 16 of S, experimental value 525 2 (MH
+).
Instance 928: preparation (4-oxyethyl group-phenyl)-{ 4-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone (compd A 184).
To being furnished with N
21-(2-fluoro-4-methylsulfonyl-phenyl)-4-(piperidin-4-yl oxygen base)-1H-pyrazolo [3,4-d] pyrimidine (50mg, 0 117mmol), triethylamine (65 μ l) and DMF (0 8mL) pack in the 50mL round-bottomed flask of inlet.Reaction flask is immersed in the ice bath.With 4-oxyethyl group-Benzoyl chloride 99min. (24mg, 0 129mmol) add in the solution and under 0 ℃ at N
2In mixture is stirred 2h.After transforming fully through all initial amine of LCMS indication, end to finish reaction through water.Reaction mixture is concentrated and passes through EtOAc is used as the tubing string purification by chromatography generation compd A 184 of scrub solution in a vacuum.
1HNMR(CDCl
3，400MHz)δ1?43(t，3H)，1?96(m，2H)，2?17(m，2H)，3?13(s，3H)，3?55(m，2H)，4?06(m，2H)，4?12(m，2H)，5?71(m，1H)，6?92(d，2H)，7?43(d，2H)，7.92(m，3H)，8?33(s，1H)，8?62(s，1H)。C
26H
26FN
5O
5The accurate mass calculated value 539.16 of S, experimental value 540.2 (MH
+).
Instance 929: preparation (5-butyl-pyridine-2-yl)-{ 4-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone (compd A 190).
To be similar to instance 925 described modes, prepare compd A 190 through the preparation HPLC purifying.
1H?NMR(CDCl
3，400MHz)δ0.96(t，3H)，1.41(m，2H)，1?67(m，2H)，2?00(m，1H)，2?14(m，2H)，226(m，1H)，2?76(t，2H)，3.13(s，3H)，3?46(m，1H)，3?74(m，3H)，3.83(m，1H)，4.16(m，1H)，5.75(m，1H)，7?68(d，1H)，7?89(m，1H)，7.95(m，3H)，8.34(s，1H)，8.62(s，1H)，8?63(s，1H)。C
27H
29FN
6O
4The accurate mass calculated value 552 20 of S, experimental value 553 4 (MH
+).
Instance 930: preparation { 4-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-(5-isopropoxy methyl-pyridine-2-yl)-ketone (compd A 192).
2-chloro-5-isopropoxy methyl-pyridine (0.12g, 0 66mmol), Zn (CN) pack in the microwave reaction test tube
2(0 077g, 0 66mmol), wantonly (triphenylphosphinyl) two palladiums (76mg, 0.066mmol), DMF (2mL).Under 180 ℃, reaction mixture is heated 5min.The gained mixture is dissolved in CH
2Cl
2/ H
2O.With CH
2Cl
2Dry and the concentrated crude product that produces of layer.Through using the tubing string purification by chromatography crude product of 30%EtOAc/ hexane.
1HNMR(CDCl
3，400MHz)δ126(d，6H)，373(m，1H)，459(s，2H)，768(d，1H)，785(m，1H)，867(s，1H)。C
10H
12N
2The accurate mass calculated value 176 09 of O, experimental value 177.2 (MH
+).
Step 2: preparation 5-isopropoxy methyl-pyridine-2-formic acid.
In the 25mL round-bottomed flask, pack into ethanol (4mL) solution of 5-isopropoxy methyl-pyridine-2-nitrile (1g, 5 7mmol).Ethanol (6mL) solution that adds KOH (16g, 28 36mmol).Make mixture reflux overnight and make it be cooled to room temperature.In the gained colloidal mixture, add H
2O is also with 6mL 10%HCl acidifying.Extract aqs soln with EtOAc.Make the dry and concentrated thick 5-isopropoxy methyl-pyridine-2-formic acid that produces of organic extract.Through using 20% MeOH/CH
2Cl
2The tubing string chromatography be further purified crude product.
1H?NMR(CDCl
3，400MHz)δ1.26(d，6H)，3.74(m，1H)，4.63(s，2H)，7?94(d，1H)，8?21(m，1H)，8?60(s，1H)。C
10H
13NO
3Accurate mass calculated value 195 09, experimental value 196 2 (MH
+).
Step 3: preparation { 4-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-(5-isopropoxy methyl-pyridine-2-yl)-ketone (compd A 192).
To be similar to instance 925 described modes, prepare compd A 192 through the preparation HPLC purifying.
1H?NMR(CDCl
3，400MHz)δ1?25(d，6H)，1?96(m，1H)，2?07(m，1H)，2?15(m，1H)，2.25(m，1H)，3?13(s，3H)，3?55(m，1H)，3?73(m，3H)，3.90(m，1H)，4?22(m，1H)，4?58(s，2H)，5?73(m，1H)，7?68(d，1H)，7?86(m，1H)，7?95(m，3H)，8?33(s，1H)，8?60(d，1H)，8?63(s1H)。C
28H
30FN
5O
5The accurate mass calculated value 567 20 of S, experimental value 568 4 (MH
+).
Instance 931: preparation { 4-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-(5-isopropoxy-pyridine-2-yl)-ketone (compd A 194).
To be similar to instance 930 described modes, prepare 5-isopropoxy-pyridine-2-formic acid through the tubing string purification by chromatography.
1HNMR(CDCl
3，400MHz)δ1?41(d，6H)，4?70(m，1H)，7.33(m，1H)，8?16(d，1H)，8?24(d，1H)。C
9H
11NO
3Accurate mass calculated value 181 07, experimental value 1822 (MH
+).
To be similar to instance 925 described modes, prepare compd A 194 through the preparation HPLC purifying.
1H?NMR(CDCl
3，400MHz)δ1?42(d，6H)，2?06(m，1H)，2?09(m，1H)，2?18(m，1H)，2?25(m，1H)，3?13(s，3H)，3?56(m，1H)，3?83(m，2H)，4?16(m，1H)，4?70(m，2H)，5?75(m，1H)，7?45(d，1H)，7.71(d，1H)，7?95(m，3H)，8.34(s，1H)，8?38(d，1H)，8.64(s，1H)。C
26H
27FN
6O
5The accurate mass calculated value 554 17 of S, experimental value 555 4 (MH
+).
Instance 932. preparation 4-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-5 '-isopropoxy-3,4,5,6-tetrahydrochysene-2H-[1,2 '] dipyridyl (compd A 201).
Is being furnished with N
2Pack in the 50mL round-bottomed flask of inlet dividing plate stirring rod, NaH (in the MO 60%, 364mg, 0.91mmol) with 5 '-isopropoxy-3,4,5,6-tetrahydrochysene-2H-[1,2 '] dipyridyl-4-alcohol (215mg, 0 91mmol).With THF (anhydrous, 3mL) add in the mixture.At room temperature with gained suspension-s stir about 30min.Then add a 4-chloro-1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine (297mg, 0 91mmol).At room temperature at N
2Down with mixture stirred overnight and gained slurries little band yellow that becomes.With CH
2Cl
2Add in the slurries and filtration.To filtrate to concentrate in a vacuum and produce crude product.Through preparation HPLC its purifying generation is the beige solid and wants product.
1H?NMR(CDCl
3，400MHz)δ1?36(d，6H)，2.17(m，2H)，2?30(m，2H)，3?13(s，3H)，3?74(m，2H)，3?97(m，2H)，4?50(m，1H)，5?76(m，1H)，7?04(d，1H)，7.60(m，1H)，7?87(m，1H)，7?94(m，3H)，8?34(s，1H)，8?64(s，1H)。C
26H
28FN
5O
4The accurate mass calculated value 52518 of S, experimental value 5262 (MH
+).
Instance 933 preparation 1-(2-fluoro-4-methylsulfonyl-phenyl)-4-[1-(4-trifluoromethoxy-phenyl)-piperidin-4-yl oxygen base]-1H-pyrazolo [3,4-d] pyrimidines (compd A 203).
To be similar to instance 932 described modes, prepare compd A 203 through the preparation HPLC purifying.
1H?NMR(CDCl
3，400MHz)δ2.46(m，2H)，2?50(m，2H)，3?14(s，3H)，3?60(m，2H)，3?78(m，2H)，5.79(m，1H)，7?36(d，2H)，7?57(d，2H)，7?95(m3H)，8?40(s，1H)，8?66(s，1H)，11?15(m，2H)。C
24H
21F
4N
5O
4The accurate mass calculated value 551.13 of S, experimental value 552.2 (MH
+).
Instance 934: preparation 1-(2-fluoro-4-methylsulfonyl-phenyl)-4-[1-(3-trifluoromethoxy-phenyl)-piperidin-4-yl oxygen base]-1H-pyrazolo [3,4-d] pyrimidine (compd A 207).
To be similar to instance 932 described modes, prepare compd A 207 through the preparation HPLC purifying.
1H?NMR(CDCl
3，400MHz)δ2?29(m，2H)，2?49(m，2H)，314(s，3H)，3?48(m，2H)，3?73(m，2H)，5?74(m，1H)，7?06(d，1H)，7?14(s，1H)，7?27(m，1H)，7?45(t，1H)，7?95(m，3H)，8?38(s，1H)，8?66(s，1H)，8?82(m，2H)。C
24H
21F
4N
5O
4The accurate mass calculated value 551 13 of S, experimental value 552.2 (MH
+).
Instance 935: preparation 5 '-fluoro-4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-3,4,5,6-tetrahydrochysene-2H-[1,2 '] dipyridyl (compd A 130).
The general process of the palladium catalytic activation of the nitrogen of aryl bromide and piperidines.
In 5mL tapered microwave bottle, add Pd continuously
2(dba)
3(25mol%), Tetrafluoroboric acid 1; 3-two (2; 6-two-i-propyl group phenyl)-4,5-glyoxalidine (5mol%), diox (anhydrous, every 0.3mmol piperidines matrix adds 1mL), piperidines matrix (1.0 equivalent), aryl bromide (0 9-13 equivalent) and KOt-Bu (10M solution among the THF, 35 equivalents).At N
2In with bottle sealing and at 120 ℃ to 130 ℃ down through carry out microwave radiation heating 10-40min (through the LC/MS monitoring).Reaction mixture is cooled to room temperature also with EtOAc (25mL) and H
2O (25mL) dilution.Said layer is mixed and separates, and extract back with EtOAc (25mL) and to contain water.To make up organism through MgSO
4Dry, filtration and concentrated.Through the reverse hplc purified product.
LunaC18 post (10 μ, 250 x 212mm), H
25% (volume ratio) CH among the O (containing 1% volume ratio TFA)
3CN (containing 1% volume ratio TFA) gradient is to 95%H
2O, 20mL/min, λ=280nm.
5 '-fluoro-4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [34-d] pyrimidine-4-base oxygen base]-3,4,5, the HPLC/MS of 6-tetrahydrochysene-2H-[1,2 '] dipyridyl (compd A 130):
YMC
TMThe ODS-AC18 post (5 μ, 50x46mm), H
25% volume ratio CH among the O (containing 1% volume ratio TFA)
3CN (containing 1% volume ratio TFA) gradient is to H
299% volume ratio CH among the O
3CN, 35mL/min, t
r=1.79min, ESI
+=387.3 (M+H).
Instance 936: preparation 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-5 '-methyl-3,4,5,6-tetrahydrochysene-2H-[1,2 '] dipyridyl (compd A 131).
To be similar to instance 935 described modes, prepare compd A 131 through the preparation HPLC purifying.HPLC/MS
The PrevailC18 post (5 μ, 50x46mm), H
25% volume ratio CH among the O (containing 1% volume ratio TFA)
3CN (containing 1% volume ratio TFA) gradient is to H
299% volume ratio CH among the O
3CN, 3.5mL/min, t
r=1 82min, ESI
+=465 2 (M+H).
Instance 937: preparation 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-6 '-trifluoromethyl-3,4,5,6-tetrahydrochysene-2H-[1,2 '] dipyridyl (compd A 132).
To be similar to instance 9.35 described modes, prepare compd A 132 through the preparation HPLC purifying.HPLC/MS
The PrevailC18 post (5 μ, 50x46mm), H
25% volume ratio CH among the O (containing 1% volume ratio TFA)
3CN (containing 1% volume ratio TFA) gradient is to H
299% volume ratio CH among the O
3CN, 35mL/min, t
r=3 00min, ESI
+=519 3 (M+H).
Instance 938: preparation (5 '-fluoro-3,4,5,6-tetrahydrochysene-2H-[1,2 '] dipyridyl-4-yl)-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-yl]-amine (compd A 138).
To be similar to instance 935 described modes, prepare compd A 138 through the preparation HPLC purifying.HPLC/MS
The PrevailC18 post (5 μ, 50x21mm), H
25% volume ratio CH among the O (containing 1% volume ratio TFA)
3CN (containing 1% volume ratio TFA) gradient is to H
299% volume ratio CH among the O
3CN, 0 75mL/min, t
r=162min, ESI
+=4683 (M+H).
Instance 939: preparation (6-chloro-pyridin-3-yl)-{ 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone (compd A 143).
The general process of 1-(4-methylsulfonyl-phenyl)-4-(piperidin-4-yl oxygen base)-1H-pyrazolo [3,4-d] pyrimidine hydrochloride and carboxylic acid coupling
To DMF (15mL) and Et
3N (45 μ L; 0 33mmol) adds the carboxylic acid of wanting in the 1-in (4-methylsulfonyl-phenyl)-4-(piperidin-4-yl oxygen base)-1H-pyrazolo [3,4-d] pyrimidine hydrochloride (35mg, 0 086mmol) solution; Compd A 143 desired acid are 6-chloro-nicotinic acid (0 11mmol; 13 equivalents), then add HATU (49mg, 0 129mmol).At room temperature with the reactant stirred overnight and use CH
3The CN dilution is also filtered.Through reverse hplc direct purification product:
The HPLC/MS of (6-chloro-pyridin-3-yl)-{ 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone (compd A 143)
YMC
TMODS-AC18 post (5 μ, 50x 46mm), H
25% volume ratio CH among the O (containing 1% volume ratio TFA)
3CN (containing 1% volume ratio TFA) gradient is to H
299% volume ratio CH among the O
3CN, 35mL/min, t
r=256min, ESI
+=5130 (M+H).
Instance 940: preparation (5-chloro-pyridin-3-yl)-4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone (compd A 144).
To be similar to instance 939 described modes, prepare compd A 144 through the preparation HPLC purifying.HPLC/MS
YMC
TMThe ODS-AC18 post (5 μ, 50x46mm), H
25% volume ratio CH among the O (containing 1% volume ratio TFA)
3CN (containing 1% volume ratio TFA) gradient is to H
299% volume ratio CH among the O
3CN, 35mL/min, t
r=2 61min, ESI
+=513 0 (M+H).
Instance 9.41: preparation { 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-(1-methyl-3-Trifluoromethyl-1 H-pyrazoles-4-yl)-ketone (compd A 145).
To be similar to instance 939 described modes, prepare compd A 145 through the preparation HPLC purifying.HPLC/MS
YMC
TMThe ODS-AC18 post (5 μ, 50x46mm), H
25% volume ratio CH among the O (containing 1% volume ratio TFA)
3CN (containing 1% volume ratio TFA) gradient is to H
299% volume ratio CH among the O
3CN, 35mL/min, t
r=258min, ESI
+=5501 (M+H).
Instance 942: preparation (2-chloro-pyridin-4-yl)-{ 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone (compd A 146).
To be similar to instance 939 described modes, prepare compd A 146 through the preparation HPLC purifying.HPLC/MS
YMC
TMODS-AC18 post (5 μ, 50 x 4.6mm), H
25% volume ratio CH among the O (containing 1% volume ratio TFA)
3CN (containing 1% volume ratio TFA) gradient is to H
299% volume ratio CH among the O
3CN, 35mL/min, t
r=258min, ESI
+=5131 (M+H).
Instance 943: preparation (4-hydroxyl-3-methoxyl group-phenyl)-{ 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone (compd A 147).
To be similar to instance 939 described modes, prepare compd A 147 through the preparation HPLC purifying.HPLC/MS
YMC
TMODS-AC18 post (5 μ, 50 x 46mm), H
25% volume ratio CH among the O (containing 1% volume ratio TFA)
3CN (containing 1% volume ratio TFA) gradient is to H
299% volume ratio CH among the O
3CN, 35mL/min, t
r=235min, ESI
+=524.3 (M+H).
Instance 9.44: preparation (4-chloro-3-nitro-phenyl)-{ 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone (compd A 148).
To be similar to instance 939 described modes, prepare compd A 148 through the preparation HPLC purifying.HPLC/MS
YMC
TMODS-AC18 post (5 μ, 50 x 46mm), H
25% volume ratio CH among the O (containing 1% volume ratio TFA)
3CN (containing 1% volume ratio TFA) gradient is to H
299% volume ratio CH among the O
3CN, 3.5mL/min, t
r=283min, ESI
+=557.3 (M+H).
Instance 945. preparation 1-{4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-3-methyl-Ding-1-ketone (Compound C 149).
To be similar to instance 939 described modes, prepare compd A 149 through the preparation HPLC purifying.HPLC/MS
YMC
TMODS-AC18 post (5 μ, 50 x 4.6mm), H
25% volume ratio CH among the O (containing 1% volume ratio TFA)
3CN (containing 1% volume ratio TFA) gradient is to H
299% volume ratio CH among the O
3CN, 3 5mL/min, t
r=275min, ESI
+=4580 (M+H).
Instance 946: preparation { 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [34-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-(6-pyrazol-1-yl-pyridin-3-yl)-ketone (compd A 150).
To be similar to instance 939 described modes, prepare compd A 150 through the preparation HPLC purifying.HPLC/MS
YMC
TMODS-AC18 post (5 μ, 50 x 46mm), H
25% volume ratio CH among the O (containing 1% volume ratio TFA)
3CN (containing 1% volume ratio TFA) gradient is to H
299% volume ratio CH among the O
3CN, 35mL/min, t
r=270min, ESI
+5454 (M+H).
Instance 947: preparation (2-hydroxyl-pyridin-3-yl)-{ 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone (compd A 151).
To be similar to instance 939 described modes, prepare compd A 151 through the preparation HPLC purifying.HPLC/MS
YMC
TMThe ODS-AC18 post (5 μ, 50x46mm), H
25% volume ratio CH among the O (containing 1% volume ratio TFA)
3CN (containing 1% volume ratio TFA) gradient is to H
299% volume ratio CH among the O
3CN, 35mL/min, t
r=195min, ESI
+=4953 (M+H).
Instance 948: preparation (5,6-two chloro-pyridin-3-yls)-{ 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone (compd A 152).
To be similar to instance 939 described modes, prepare compd A 152 through the preparation HPLC purifying.HPLC/MS
YMC
TMODS-AC18 post (5 μ, 50 x 46mm), H
25% volume ratio CH among the O (containing 1% volume ratio TFA)
3CN (containing 1% volume ratio TFA) gradient is to H
299% volume ratio CH among the O
3CN, 35mL/min, t
r=281min, ESI
+5469 (M+H).
Instance 949: preparation (5-bromo-pyridin-3-yl)-{ 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone (compd A 153).
To be similar to instance 939 described modes, prepare compd A 153 through the preparation HPLC purifying.HPLC/MS
YMC
TMThe ODS-AC18 post (5 μ, 50x46mm), H
25% volume ratio CH among the O (containing 1% volume ratio TFA)
3CN (containing 1% volume ratio TFA) gradient is to H
299% volume ratio CH among the O
3CN, 35mL/min, t
r=2.66min, ESI
+=559 2 (M+H).
Instance 9.50: preparation 5-{4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-carbonyl }-nicotinic acid (compd A 154).
To be similar to instance 939 described modes, prepare compd A 154 through the preparation HPLC purifying.HPLC/MS:
YMC
TMODS-AC18 post (5 μ, 50 x, 4 6mm), H
25% volume ratio CH among the O (containing 1% volume ratio TFA)
3CN (containing 1% volume ratio TFA) gradient is to H
299% volume ratio CH among the O
3CN, 35mL/min, t
r=204min, ESI
+523 3 (M+H).
Instance 9.51: preparation (1H-imidazol-4 yl)-{ 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone (compd A 155).
To be similar to instance 9.39 described modes, prepare compd A 155 through the preparation HPLC purifying.HPLC/MS
YMC
TMODS-AC18 post (5 μ, 50 x 4.6mm), H
25% volume ratio CH among the O (containing 1% volume ratio TFA)
3CN (containing 1% volume ratio TFA) gradient is to H
299% volume ratio CH among the O
3CN, 35mL/min, t
r=173min, ES]
+=468 3 (M+H).
Instance 952 preparations { 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-(6-tetramethyleneimine-1-base-pyridin-3-yl)-ketone (compd A 157).
To be similar to instance 939 described modes, prepare compd A 157 through the preparation HPLC purifying.HPLC/MS
YMC
TMODS-AC18 post (5 μ, 50 x 4.6mm), H
25% volume ratio CH among the O (containing 1% volume ratio TFA)
3CN (containing 1% volume ratio TFA) gradient is to H
299% volume ratio CH among the O
3CN, 35mL/min, t
r=2.08min, ESI
+5483 (M+H).
Instance 9.53 preparations (6-isobutyl amino-pyridine-3-yl)-{ 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone (compd A 158).
To be similar to instance 939 described modes, prepare compd A 158 through the preparation HPLC purifying.HPLC/MS:
YMC
TMODS-AC18 post (5 μ, 50 x 46mm), H
25% volume ratio CH among the O (containing 1% volume ratio TFA)
3CN (containing 1% volume ratio TFA) gradient is to H
299% volume ratio CH among the O
3CN, 35mL/min, t
r=258min, ESI
+5501 (M+H).
Instance 954 preparations (6-ethylamino-pyridin-3-yl)-{ 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone (compd A 159).
To be similar to instance 939 described modes, prepare compd A 159 through the preparation HPLC purifying.HPLC/MS
YMC
TMODS-AC18 post (5 μ, 50 x 46mm), H
25% volume ratio CH among the O (containing 1% volume ratio TFA)
3CN (containing 1% volume ratio TFA) gradient is to H
299% volume ratio CH among the O
3CN, 3.5mL/min, t
r=196min, ESI
+5223 (M+H).
Instance 955 preparations (6-ring fourth amino-pyridine-3-yl)-{ 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone (compd A 160).
To be similar to instance 939 described modes, prepare compd A 160 through the preparation HPLC purifying.HPLC/MS
YMC
TMODS-AC18 post (5 μ, 50 x 46mm), H
25% volume ratio CH among the O (containing 1% volume ratio TFA)
3CN (containing 1% volume ratio TFA) gradient is to H
299% volume ratio CH among the O
3CN, 3.5mL/min, t
r=215min, ESI
+5484 (M+H).
Instance 956 preparations (6-isopropylamino-pyridin-3-yl)-{ 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone (compd A 161).
To be similar to instance 939 described modes, prepare compd A 161 through the preparation HPLC purifying.HPLC/MS
YMC
TMODS-AC18 post (5 μ, 50 x 46mm), H
25% volume ratio CH among the O (containing 1% volume ratio TFA)
3CN contains 1% volume ratio TFA) gradient is to H
299% volume ratio CH among the O
3CN, 3.5mL/min, t
r=205min, ESI
+=5362 (M+H).
Instance 957 preparations [6-(1-ethyl-third amino)-pyridin-3-yl]-{ 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone (compd A 162).
To be similar to instance 939 described modes, prepare compd A 162 through the preparation HPLC purifying.HPLC/MS
YMC
TMThe ODS-AC18 post (5 μ, 50x46mm), H
25% volume ratio CH among the O (containing 1% volume ratio TFA)
3CN (containing 1% volume ratio TFA) gradient is to H
299% volume ratio CH among the O
3CN, 3 5mL/min, t
r=2 13min, ESI
+=550 2 (M+H).
Instance 9.58. preparation { 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-[6-(1-propyl group-Ding is amino)-pyridin-3-yl]-ketone (compd A 163).
To be similar to instance 939 described modes, prepare compd A 163 through the preparation HPLC purifying.HPLC/MS
YMC
TMODS-AC18 post (5 μ, 50 x 4.6mm), H
25% volume ratio CH among the O (containing 1% volume ratio TFA)
399% volume ratio CH in CN (containing 1% volume ratio TFA) gradient to the water
3CN, 35mL/min, t
r=2.40min, ESI
+=578.5 (M+H).
Instance 959: preparation 5-benzyloxy-2-{4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-carbonyl }-pyrans-4-ketone (compd A 164).
To be similar to instance 939 described modes, prepare compd A 164 through the preparation HPLC purifying.HPLC/MS
YMC
TMThe ODS-AC18 post (5 μ, 50x4.6mm), H
25% volume ratio CH among the O (containing 1% volume ratio TFA)
3CN (containing 1% volume ratio TFA) gradient is to H
299% volume ratio CH among the O
3CN, 35mL/min, t
r=264min, ESI
+=602 3 (M+H).
Instance 960: preparation benzo [c] isoxazole-3-base-{ 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone (compd A 165).
To be similar to instance 9.39 described modes, prepare compd A 165 through the preparation HPLC purifying.HPLC/MS
YMC
TMODS-AC18 post (5 μ, 50 x 46mm), H
25% volume ratio CH among the O (containing 1% volume ratio TFA)
3CN (containing 1% volume ratio TFA) gradient is to H
299% volume ratio CH among the O
3CN, 35mL/min, t
r=2 85min, ESI
+=519 4 (M+H).
Instance 961: preparation (4-chloro-pyridine-2-yl)-{ 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone (compd A 166).
To be similar to instance 939 described modes, prepare compd A 166 through the preparation HPLC purifying.HPLC/MS
PrevailC18 post (5 μ, 50 x 46mm), H
25% volume ratio CH among the O (containing 1% volume ratio TFA)
3CN (containing 1% volume ratio TFA) gradient is to H
299% volume ratio CH among the O
3CN, 35mL/min, t
r=262min, ESI
+=513.2 (M+H).
Instance 962: preparation 1-{4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-Ding-2-ketone (Compound C 168).
1-in diox (15mL) (4-methylsulfonyl-phenyl)-4-(piperidin-4-yl oxygen base)-1H-pyrazolo [34-d] pyrimidine hydrochloride (30 0mg, 0 073mmmol) and Et
3N (35 μ L) solution adds bromoketone (22 μ L, 0 219mmol).Under 100 ℃ with mixture carry out microwave radiation heating 10min.Mixture is used CH
3CN (3mL) dilution is also passed through the reverse hplc purifying:
LunaC18 post (10 μ, 250 x 212mm), H
25% (volume ratio) CH among the O (containing 1% volume ratio TFA)
3CN (containing 1% volume ratio TFA) gradient is to 95%H
2O, 20mL/min, λ=214nm produces the separated solid compd A 168 that is white in color (78mg, 0 014mmol, productive rate 19%).HPLC/MS
PrevailC18 post (5 μ, 50 x 46mm), H
25% volume ratio CH among the O (containing 1% volume ratio TFA)
399% volume ratio CH in CN (containing 1% volume ratio TFA) gradient to the water
3CN, 35mL/min, t
r=169min, ESI
+=444 3 (M+H).
Instance 963, preparation 2-{4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-carbonyl }-pyrans-4-ketone (compd A 182).
To be similar to instance 939 described modes, prepare compd A 182 through the preparation HPLC purifying.HPLC/MS
PrevailC18 post (5 μ, 50 x 46mm), H
25% volume ratio CH among the O (containing 1% volume ratio TFA)
399% volume ratio CH in CN (containing 1% volume ratio TFA) gradient to the water
3CN, 3 5mL/min, t
r=2 14min, ESI
+=496.2 (M+H).
Instance 964: preparation 5 '-bromo-4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-3,4; 5,6-tetrahydrochysene-2H-[1,2 '] dipyridyl (compd A 206) and 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3; 4-d] pyrimidine-4-base oxygen base]-5 '-trifluoromethyl-3,4,5; 6-tetrahydrochysene-2H-[1,2 '] dipyridyl (compd A 208).
The preparation method of step 1:2-chloropyridine and the substituted general process of 4-hydroxy piperidine aromatic series.
Under 160 ℃ under carry out microwave radiation heating the piperidines in the Virahol (15mL)-4-alcohol (100mg, 0 99mmol), the 2-chloropyridine of wanting (0 99mmol, 10 equivalents) and DIPEA (345 μ L, 198mmol) solution 25h.Produce institute through silica gel chromatography direct purification reactant and want 3,4,5,6-tetrahydrochysene-2H-[1; 2 '] dipyridyl-4-alcohol (and use 5-bromo-2-chloropyridine, separate productive rate 27%, 69 1mg, 5 of 0 27mmol '-bromo-3; 4,5,6-tetrahydrochysene-2H-[1,2 '] dipyridyl-4-alcohol; Use 5-trifluoromethyl-2-chloropyridine, separate productive rate 62%, 150 1mg, 5 of 0 61mmol '-trifluoromethyl-3,4,5,6-tetrahydrochysene-2H-[1,2 '] dipyridyl-4-alcohol).
5 '-bromo-3,4,5, the HPLC/MS of 6-tetrahydrochysene-2H-[1,2 '] dipyridyl-4-alcohol:
PrevailC18 post (5 μ, 50 x46mm), H
25% volume ratio CH among the O (containing 1% volume ratio TFA)
3CN (containing 1% volume ratio TFA) gradient is to H
299% volume ratio CH among the O
3CN, 35mL/min, t
r=117min, ESI
+2589 (M+H).
5 '-trifluoromethyl-3,4,5, the HPLC/MS of 6-tetrahydrochysene-2H-[1,2 '] dipyridyl-4-alcohol:
Prevail C18 post (5 μ, 50 x 46mm), H
25% volume ratio CH among the O (containing 1% volume ratio TFA)
3CN (containing 1% volume ratio TFA) gradient is to H
299% volume ratio CH among the O
3CN, 35mL/min, t
r=1.47min, ESI
+=2471 (M+H).
At room temperature at N
2In to want 5 '-bromo-3,4,5, THF (15mL) solution of 6-tetrahydrochysene-2H-[1,2] dipyridyl-4-alcohol (69mg, 0 27mmol, 10 equivalents) adds NaH (60% weight ratio dispersion liquid in the MO, 25mg, 0 62mmol, 23 equivalents).After stirring 5min, add 4-chloro-1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine (64 1mg, 0 21mmol) and at room temperature reactant is stirred 2h.Mixture is used H
2O (0 5mL) and CH
3CN (3 0mL) dilution is also passed through the reverse hplc direct purification:
LunaC18 post (10 μ, 250 x 5%), H
25% (volume ratio) CH among the O (containing 1% volume ratio TFA)
3CN (containing 1% volume ratio TFA) gradient is to 95%H
2O, 20mL/min, λ=214nm produces the solid compd A 206 (2 5mg, 0.0056mmol, productive rate 3%) that is white in color.
Compd A 206: preparation HPLC/MS:
Prevail C18 post (5 μ, 50 x 46mm), H
25% volume ratio CH among the O (containing 1% volume ratio TFA)
3CN (containing 1% volume ratio TFA) gradient is to H
299% volume ratio CH among the O
3CN, 35mL/min, t
r=278min, ESI
+=531 2 (M+H).
Compd A 208: preparation HPLC/MS:
PrevailC18 post (5 μ, 50 x, 2 1mm), H
25% volume ratio CH among the O (containing 1% volume ratio TFA)
3CN (containing 1% volume ratio TFA) gradient is to H
299% volume ratio CH among the O
3CN, 0.75mL/min, t
r=286min, ESI
+=519 3 (M+H).
Instance 965: preparation 1-[2-fluoro-4-(methylsulfonyl) phenyl]-4-[[1-(3-sec.-propyl-1,2,4-oxadiazole-5-yl)-3-pyrrolidyl] oxygen base]-1H-pyrazolo-[3,4-d] pyrimidine hydrochloride (compd A 136).
Step 1: preparation (RS)-3-hydroxyl-1-[(3-sec.-propyl-1,2,4-oxadiazole-5-yl) methyl] tetramethyleneimine.
With 5-chloromethyl-3-sec.-propyl-[1,2,4] oxadiazoles (and 16g, 10mmol) with (RS)-(960mg, the pure combination of mixture 11mmol) is with MeCN (10mL) purifying and add K for the 3-hydroxyl pyrrolidine
2CO
3(2.75g, 20mmol).Under 65 ℃,, and take advantage of cold filtration with mixture heating up 1h.Remove solvent and use CH
2Cl
2Dissolving resistates and water flushing.Make organic extract through MgSO
4Drying removes solvent, and also filters to remove quaternary ammonium by product in a small amount with ether dissolving resistates.Remove solvent from filtrating and produce (RS)-3-hydroxyl-1-[(3-sec.-propyl-1,2, the 4-oxadiazole-5-yl) methyl] tetramethyleneimine (172g, productive rate 82%) that is amber oily:
1HNMR (DMSO-d
6) δ 476 (d, 1H, J=45H z), 419 (m, 1H), 390 (s, 2H), 305 (m, 1H), 279 (m, 1H), 269 (m, 1H), 253 (m, 1H), 243 (m, 1H), 198 (m, 1H), 154 (m, 1H), 125 (d, 6H, J=6.8Hz), MSm/z 212 1 (M
+).
Step 2: preparation 1-[2-fluoro-4-(methylsulfonyl) phenyl]-4-[[1-(3-sec.-propyl-1,2,4-oxadiazole-5-yl)-3-pyrrolidyl] oxygen base]-1H-pyrazolo-[3,4-d] pyrimidine hydrochloride (compd A 136).
At N
2In (422mg, anhydrous THF (5mL) solution 20mmol) adds NaH (MO dispersion liquid 60%, 480mg, anhydrous THF suspension-s 12mmol) through stirring with 1-(3-sec.-propyl-[1,2,4] oxadiazole-5-ylmethyls)-tetramethyleneimine-3-alcohol.After stirring 10min, (654mg 20mmol), and stirs 18h with reaction mixture to add 4-chloro-1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine.Then water stopped reaction and extract with ether.Use the normal saline washing organic extract, make it through MgSO
4Dry and with solvent removal.Incline to, make up and the volume minimizing with resistates wet-milling in hot ether (3X10mL) and with the ether washing fluid.By ether/CH
2Cl
241 crystallizations produce the 425mg white solid.With the resistates combination of filtrating and ether washing fluid and through flash chromatography (CH
2Cl
2In 0 5%7N NH
3/ MeOH) producing the 100mg product again, ultimate production is 525mg (productive rate 53%).Product is dissolved in CH
2Cl
2And, then remove the compd A 136 (570mg) that solvent produces the powder that is white in color with 1N HCl/ ether (3.0mL) processing:
1H NMR (CDCl
3) δ 8 62 (s, 1H), 8 34 (s, 1H), 7.95 (m, 3H), 5 81 (m, 1H), 4 02 (m, 2H), 3 24 (m, 1H), 3 15 (s, 3H), 3 10 (m, 3H), 2 79 (m, 1H), 2 54 (m, 1H), 2 20 (m, 1H), 1 35 (d, 6H, J=6 8Hz), MS m/z 502 0 (M
+).
Instance 966: preparation 1-[4-(methylsulfonyl) phenyl]-4-[[1-[(4-trifluoromethoxy) phenyl]-4-piperidyl] oxygen base]-1H-pyrazolo-[3,4-d] pyrimidine (compd A 202).
Step 1: preparation 4-hydroxyl-1-(4-trifluoromethoxy-)-Phenylpiperidine.
At N
2In make 4-(trifluoromethoxy) bromobenzene (241g; 10.0mmol), 4-hydroxy piperidine (1.21g; 120mmol), three (diphenylmethylene ethyl ketone) two palladiums (O) (137mg, 0.15mmol) and the mixture of 2-(two-tertiary butyl phosphino-) biphenyl (107mg, 0 36mmol) and two (trimethyl silyl) acid amides lithium (10M among the THF; 22mL, 22mmol) chemical combination.Under 65 ℃, reaction mixture is heated 2h, then with its be cooled to envrionment temperature and with 1N HCl (35mL) end to the pH value be 7.With EtOAc (20mL) extraction gained mixture, and use the normal saline washing organic extract, make it through MgSO
4Dry and with solvent removal.Make resistates stand flash chromatography (CH
2Cl
2Middle 2%7N formic acid ammonia CH
2Cl
2), when solvent removal, produce wax shape, amber solid (14g, productive rate 54%).
1HNMR(CDCl
3)δ702(d，2H，J＝87Hz)，683?(d，2H，J＝84Hz)，3.79(m，1H)，3?45(m，2H)，2?86(m，2H)，1?94(m，2H)，1?62(m，2H)，1.49(s，1H)，MS?m/z261?9(M
+)。
Step 2: preparation 1-[4-(methylsulfonyl) phenyl]-4-[[1-[(4-trifluoromethoxy) phenyl]-4-piperidyl] oxygen base]-1H-pyrazolo-[3,4-d] pyrimidine (compd A 202).
Through being similar to instance 965 said methods by 4-hydroxyl-1-(4-trifluoromethoxy-)-Phenylpiperidine and 4-chloro-1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3; 4-d] pyrimidine synthetic compound A202; Yet at room temperature after the stirred overnight, require that it is heated 1h down at 65 ℃ and accomplish to order about reaction.React in an identical manner, but through coming separated free alkali from the EtOAc crystallization.When preparation HCl salt, obtain white solid (570mg, productive rate 50%):
1H NMR (DMSO-d
6) δ 8 82 (s, 1H), 8 70 (s, 1H), 8 56 (d, 2H, 7=94Hz), 8.16 (d, 2H, 7=94Hz); 7 55 (m, 2H), 7.41 (d, 2H, J=8 2Hz), 5 71 (m, 1H), 3 71 (m, 2H); 3 46 (m, 2H), 3 29 (s, 3H), 236 (m, 2H), 2 19 (m, 2H), MSm/z534 2 (M
+).
Instance 967: preparation (compd A 238).
Make and be solid compd A 203 to be similar to instance 96 described modes.C
17H
18FN
5O
3The accurate mass calculated value 391 1 of S, experimental value 392.2 (MH
+).
Instance 968: preparation 4-[(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base sulfenyl]-piperidines-1-t-butyl formate (compd A 107).
With K
2CO
3Add in DMF (50mL) solution of 4-sulfydryl-piperidines-1-t-butyl formate (3.09g, 14 22mmol).After at room temperature stirring 45min, add 4-chloro-1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine (4 65g, 14 22mmol).Stir behind the 1h with the ethyl acetate extraction reactant and use water washing.Some product is separated out in organic layer.It is collected through filtering.To remain organic layer through anhydrous MgSO
4Drying is filtered and the concentrated solid compd A 107 that is white in color that produces.
1H?NMR(CDCl
3，400MHz)δ1?48(9H，s)，1.77(2H，m)，2?18(2H，m)，3.20-3?13(5H，m)，3?99(2H，m)，4?42(1H，m)，7?95(3H，m)，8?30(1H，s)，878(1H，s)。C
22H
26FN
5O
4S
2Accurate mass calculated value 507 1, experimental value 508.3 (MH
+).
Instance 969: preparation 4-[(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base sulfenyl]-piperidines-1-isopropyl formate (compd A 214).
With 1, the 4MHCl in the 4-diox (40mL) handles 4-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base sulfenyl]-piperidines-1-t-butyl formate (3 54g, 6 97mmol).After at room temperature stirring 2h, collect 1-(2-fluoro-4-methylsulfonyl-phenyl)-4-(piperidin-4-yl sulfenyl)-1H-pyrazolo [3,4-d] pyrimidine hydrochloride through filtering.To the mixture of 1-(2-fluoro-4-methylsulfonyl-phenyl)-4-(piperidin-4-yl sulfenyl)-1H-pyrazolo [3,4-d] pyrimidine hydrochloride (30g, 6 76mmol) in DMF (27mL) add triethylamine (2 05g, 20.28mmol).After stirring 30mm, add the 1.0M toluene solution of isopropyl chlorocarbonate (7 44mmol) and reactant is stirred 2h to reaction.HCl salts out and through filtering it is removed.With ETHYLE ACETATE (100mL) extraction filtrating and water (4x 100mL) washing.With organism through anhydrous MgSO
4Drying is filtered and the concentrated in a vacuum solid compd A 214 that is white in color that produces.
1HNMR(CDCl
3，400MHz)δ1.27(d，J＝6?3Hz，6H)，1.77(2H，m)，2?18(2H，m)，3.13(3H，s)，3.21(2H，m)，4.04(2H，m)，4.48-4.40(1H，m)，4.99-4.90(1H，m)，7?98-7?52(3H，m)，8?30(1H，s)，8?79(1H，s)。C
21H
24FN
5O
4S
2Accurate mass calculated value 493 1, experimental value 494 3 (MH
+).
Instance 970: the preparation of acid and amine coupling general process.
At room temperature with carboxylic acid (0.139mmol) among the DMF (6mL) and HATU (53mg, 0 139mmol) solution stirring 1h.In solution, add triethylamine (34mg, 0 332mmol) and amine, for example 1-(4-methylsulfonyl-phenyl)-4-(piperidin-4-yl oxygen base)-1H-pyrazolo [3,4-d] pyrimidine (40mg, 0 107mmol).At room temperature after the stirred overnight, with DCM (5mL) extractive reaction thing, with 1M water-based Hydrocerol A (5mL) washing, then water (3x5mL) washs with it.Through Na
2SO
4Dry organic layer.Organic layer is concentrated in a vacuum and it is produced the compound of wanting as tfa salt through the HPLC purifying.
To be similar to method mentioned above with representative The compounds of this invention below the preparation of said general process:
{ 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-(5-methyl-pyridin-3-yl)-ketone (compd A 18);
{ 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-(6-trifluoromethyl-pyridin-3-yl)-ketone (compound A-13 4);
2-(5-bromo-pyridin-3-yl)-1-{4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ethyl ketone (compd A 169),
(6-fluoro-pyridine-2-yl)-{ 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone (compd A 170);
(6-chloro-pyridine-2-yl)-{ 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone (compd A 172),
{ 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-[5-(2-methyl-tetramethyleneimine-1-ylmethyl)-pyridin-3-yl]-ketone (compd A 174);
5-{4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-carbonyl }-cigarette nitrile (compd A 176); With
5-{4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-carbonyl }-pyridine-2-methyl-formiate (compd A 195).Following table is showed the corresponding MS data of compd A 18, A34, A169, A170, A172, A174, A176 and A195.
The MS data
| Compound number | Chemical formula | Accurate mass | Experimental value (MH +) |
| A18 | C 24H 24N 6O 4S | 492.16 | 493.4 |
| A34 | C 24H 21F 3N 6O 4S | 546?13 | 547?3 |
| A169 | C 24H 23BrN 6O 4S | 570?07 | 573?2 |
| A170 | C 23H 21FN 6O 4S | 496?13 | 497?1 |
| A172 | C 23H 21ClN 6O 4S | 512?1 | 513?2 |
| A174 | C 29H 33N 7O 4S | 575?23 | 576.3 |
| A176 | C 24H 21N 7O 4S | 503?14 | 504?2 |
| A195 | C 25H 24N 6O 6S | 536?15 | 537?2 |
Instance 971: the general preparation of alkylation process.
1-(4-methylsulfonyl-phenyl)-4-(piperidin-4-yl oxygen base) in DMF (1 5mL)-1H-pyrazolo [3,4-d] pyrimidine mixture adds triethylamine (38mg, 0 379mmol) and the alkyl bromide of wanting (0 159mmol).At room temperature after the stirred overnight, use CH
3CN, CH
3OH and H
2O diluting reaction thing also produces the compound of wanting as tfa salt through the HPLC purifying.
To be similar to method mentioned above with representative The compounds of this invention below the preparation of said general process:
{ 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ETHYLE ACETATE (compd A 196):
1-(4-chloro-phenyl)-2-{4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ethyl ketone (compd A 199);
2-{4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-1-(3-trifluoromethyl-phenyl)-ethyl ketone (compd A 200),
1-(4-chloro-3-methyl-phenyl)-2-{4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ethyl ketone (compd A 204),
1-(3,4-two chloro-phenyl)-2-{4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ethyl ketone (compd A 205);
1-(2,4-dimethoxy-phenyl)-2-{4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ethyl ketone (compd A 209);
1-(4-difluoro-methoxy-phenyl)-2-{4-[1-{4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ethyl ketone (compd A 210); With
1-(4-diethylin-phenyl)-2-{4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ethyl ketone (compd A 211).
Following table is showed the corresponding MS data of compd A 196, A199, A200, A204, A205, A209, A210 and A211.
The MS data
| Compound number | Chemical formula | Accurate mass | Experimental value (MH +) |
| A196 | C 21H 25N 5O 5S | 459.16 | 460.3 |
| A199 | C 25H 24ClN 5O 4S | 525?12 | 526?4 |
| A200 | C 26H 24F 3N 5O 4S | 559?15 | 560?3 |
| A204 | C 26H 26ClN 5O 4S | 539?14 | 540?1 |
| A205 | C 25H 23Cl 2N 5O 4S | 559?08 | 560.2 |
| A209 | C 27H 29N 5O 6S | 551?18 | 552?3 |
| A210 | C 26H 25F 2N 5O 5S | 557?15 | 558?3 |
| A211 | C 29H 34N 6O 4S | 562.24 | 563?2 |
Instance 972: preparation (5-amino-pyridine-2-yl)-{ 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone (compd A 186).
3-in 30mL DMF is amino to add HATU (673mg, 1 77mmol) and triethylamine (1mL, 7 72mmol) than clone Buddhist nun acid (3-aminopicloinic acid) (245mg, 1 77mmol) solution.Behind the 5min, add 1-(4-methylsulfonyl-phenyl)-4-(piperidin-4-yl oxygen base)-1H-pyrazolo [3,4-d] pyrimidine (HCl salt, 660mg, 1 61mmol) and mixture is stirred 45min.With 1MNaOH solution and dichloromethane extraction mixture; Make organic layer through MgSO
4Dry, filtration and concentrated.Produce the solid compd A 186 (tfa salt, 389mg, 36%) that is white in color through HPLC purifying resistates.C
23H
23N
7O
4The accurate mass calculated value 493 15 of S, experimental value 494 4 (MH
+).
Instance 973: preparation (5-amino-pyridine-2-yl)-{ 4-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone (compd A 187).
3-in 40mLDMF amino than clone Buddhist nun acid (290mg, 2.10mmol) solution add HATU (801mg, 2.11mmol) and triethylamine (1.17mL, 8.44mmol).Behind the 5min, add 1-(2-fluoro-4-methylsulfonyl-phenyl)-4-(piperidin-4-yl oxygen base)-1H-pyrazolo [3,4-d] pyrimidine (HCl salt, 660mg, 1 91mmol) and mixture is stirred 45min.Produce the solid compd A 187 (tfa salt, 1 03g, 79%) that is white in color through the HPLC purified mixture.C
23H
22FN
7O
4The accurate mass calculated value 511 14 of S, experimental value 512 2 (MH
+).
Instance 974: preparation (5-ethylamino-pyridine-2-yl)-{ 4-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone (compd A 191).
At room temperature stir (5-amino-pyridine-2-yl)-{ 4-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3 in the 7mL acetonitrile; 4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone (compd A 187-TFA salt; 500mg; 0 799mmol), monobromethane (60 μ l, 0 80mmol) and salt of wormwood (331mg, 2.39mmol) mixture.Behind the 1h, continuously stirring mixture under refluxing.Behind the 45min, do not observe to such an extent that have product to produce yet.Mixture is cooled to room temperature, adds sodium hydride dispersion (70mg, 1 75mmol) and stirring at room temperature.Behind the 90min, add more sodium hydride dispersion (70mg, 1 75mmol) and under refluxing, mixture is stirred 90min.Be buttery compd A 191 (tfa salt, 10mg, 2%) through the generation of HPLC purified mixture.C
25H
26FN
7O
4The accurate mass calculated value 539.18 of S, experimental value 540 3 (MH
+).
Instance 975: preparation { 4-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-[5-(3-methyl-Ding is amino)-pyridine-2-yl]-ketone (compd A 188).
Obtain to be buttery compd A 188 (tfa salt, 66mg, 1%) to be similar to instance 9.74 described modes.C
28H
32FN
7O
4The accurate mass calculated value 581 22 of S, experimental value 582 6 (MH
+).
Instance 976: preparation 4-[1-(4-bromo-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-isopropyl formate (compd A 220).
(465mg, 19.4mol) mixture stirs 30min with the 4-hydroxy-piperdine-1-isopropyl formate among the THF (12mL) (727mg, 3 88mmol) and sodium hydride under 60 ℃.At room temperature 1-(4-bromo-phenyl)-4-chloro-1H-pyrazolo [3,4-d] pyrimidine is added mixture and at room temperature it stirred 10h.The ethyl acetate extraction product is ended and used to the reactant water.Concentrate organic layer in a vacuum and produce the solid compd A 220 (1 3g, 81%) that is white in color.
1HNMR(CDCl
3，400MHz)δ1?19(d，6H)，1?73-1?85(m，2H)，1?98-2?08(m，2H)，3?26-3?34(m，2H)，3?78-3?87(m，2H)，4?88(h，1H)，5.54(h，1H)，7?57(d，2H)，8.07(d，2H)，8.13(s，1H)，8.55(s，1H)。C
20H
22BrN
5O
3Accurate mass calculated value 460 3, experimental value 462 3 (MH
+).
Instance 977: preparation 4-[1-(4-third amino-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-isopropyl formate (compd A 221).
General amination method.
Under 100 ℃ under microwave radiation with the [1-(4-bromo-phenyl)-1H-pyrazolo [3 of the 4-among the DMSO (2 5mL); 4-d] pyrimidine-4-base oxygen base]-piperidines-1-isopropyl formate (compd A 220,100mg, 0 22mmol), Tri N-Propyl Amine (130mg; 2 2mmol), L-proline(Pro) (46mg; 0 40mmol), cupric iodide (42mg, 0 22mmol) and salt of wormwood (71mg, 0 51mmol) mixture heating up 50min.Crude mixture is concentrated in a vacuum and produces the solid compd A 221 (6mg, 6%) that is white in color through the HPLC purifying.
1H?NMR(CDCl
3，400MHz)δ0?95(t，3H)，1?20(d，6H)，1?54-1?56(m，2H)，1?80-1?89(m，2H)，1?97-2?07(m，2H)，3?07(t，2H)，3.25-3?34(m，2H)，3?76-3?87(m，2H)，4?88(h，1H)，5?51(h，1H)，6?67(d，2H)，7?71(d，2H)，8?08(s，1H)，8?50(s，1H)。C
23H
30N
6O
3Accurate mass calculated value 438 52, experimental value 439.4 (MH
+).
Instance 9.78 preparation 4-[1-(4-isopropylamino-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-isopropyl formate (compd A 222).
Prepare compd A 222 to be similar to instance 9 77 described modes.
1HNMR(CDCl
3，400MHz)δ1.20(d，6H)，1?28(d，6H)，1?74-1?85(m，2H)，1?99-2?09(m，2H)，3?26-3?36(m，2H)，3?52-3.60(m，2H)，3?79-3?89(m，2H)，4?88(h，1H)，5?51(h，1H)，7?46(d，2H)，7?99(s，1H)，8?21(d，2H)，8?49(s，1H)。C
23H
30N
6O
3Accurate mass calculated value 438 52, experimental value 439 4 (MH
+).Instance 979: preparation 4-[1-(4-morpholine-4-base-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-isopropyl formate (compd A 227).
Prepare compd A 227 to be similar to instance 977 described modes.
1H?NMR(CDCl
3，400MHz)δ1?19(d，6H)，1?73-1.84(m，2H)，1?97-2.06(m，2H)，3?12-3.19(m，4H)，3?25-3.35(m，2H)，3?76-3?87(m，6H)，4?87(h，1H)，5?52(h，1H)，6?99(d?2H)，7?90(d，2H)，8?10(s，1H)，8?51(s，1H)。C
23H
30N
6O
4Accurate mass calculated value 466 53, experimental value 4673 (MH
+).
Instance 980: preparation 4-[1-(2-fluoro-4-isopropylamino-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-isopropyl formate (compd A 230).
Under 100 ℃ under microwave radiation with the [1-(2-fluoro-4-iodo-phenyl)-1H-pyrazolo [3 of the 4-among the DMSO (40mL); 4-d] pyrimidine-4-base oxygen base]-piperidines-1-isopropyl formate (263mg; 0 50mmol), Isopropylamine (450 μ L, 50mmol), L-proline(Pro) (86mg, 0 75mmol), cupric iodide (95mg; 0 50mmol) and salt of wormwood (207mg, 1 50mmol) mixture heating up 50min.Crude product is concentrated in a vacuum and produces the solid compd A 230 (80mg, 35%) that is white in color through the HPLC purifying.
1HNMR(CDCl
3，400MHz)δ120(d，6H)，1.26(d，6H)，1?75-1.88(m，2H)，1?98-2.09(m，2H)，3?28-3?37(m，2H)，3?55-3.63(m，1H)，3?78-3.87(m，2H)，4?88(h，1H)，5?55(h，1H)，6?90-7?08(m，2H)，7?44-7.50(m，1H)，8?17(s，1H)，8.53(s，1H)。C
23H
29FN
6O
3Accurate mass calculated value 456 51, experimental value 457 3 (MH
+).
Instance 981: preparation 4-[1-(2-fluoro-4-morpholine-4-base-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-isopropyl formate (compd A 229).
Prepare compd A 229 to be similar to instance 980 described modes.
1H?NMR(CDCl
3，400MHz)δ120(d，6H)，1?74-1.86(m，2H)，1?57-2?07(m，2H)，3?13-3?19(m，4H)，3?25-3?36(m，2H)，3?76-3?87(m，6H)，4.87(h，1H)，5?52(h，1H)，6?66-6?76(m，2H)，7?33-7.43(m，1H)，8?15(s，1H)，8?50(s，1H)。C
24H
29FN
6O
4Accurate mass calculated value 484 52, experimental value 485 4 (MH
+).
Instance 982:4-(1-{4-[4-(2-methylsulfonyl-ethyl)-piperazine-1-yl]-2-methyl-phenyl }-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base)-piperidines-1-isopropyl formate (compd A 223).
Amidized general process.
Under 120 ℃ under microwave condition with the [1-(4-iodo-2-methyl-phenyl)-1H-pyrazolo [3 of the 4-among the DMSO (2mL); 4-d] pyrimidine-4-base oxygen base]-piperidines-1-isopropyl formate (78mg; 0 15mmol), 1-(2-methylsulfonyl-ethyl)-piperazine (0 75mmol, 50 equivalents), CuI (0.15mmol, 1 equivalent), L-proline(Pro) (0 27mmol; 18 equivalents) and the solution of salt of wormwood (0 15mmol, 1 equivalent) heating 1h.Be brown thickness oily compd A 223 (5mg, 6%) through the generation of preparation type LCMS 5-95% purifying crude product.C
28H
39N
7O
5The accurate mass calculated value of S is 5853, experimental value LCMS (ESI) m/z 5866 (M+H
+, 90%).
Instance 983 preparation 4-(1-{2-methyl-4-[(tetrahydrochysene-furans-2-ylmethyl)-amino]-phenyl }-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base)-piperidines-1-isopropyl formate (compd A 224).
Prepare the compd A 224 (36.8mg, 50%) that is the peachiness powder to be similar to instance 982 described modes.C
26H
34N
5O
4The accurate mass calculated value be 494 3, experimental value LCMS (ESI) m/z 495 6 (M+H
+, 71%).
Instance 984: preparation 4-[1-(4-cyclopropylamino-2-methyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-isopropyl formate (compd A 225).
Prepare the compd A 225 that is the beige powder to be similar to instance 982 described modes.C
24H
30N
6O
3The accurate mass calculated value be 4502, experimental value LCMS (ESI) m/z 4514 (M+H
+, 97%).
Instance 985 preparation 4-{1-[4-(2-dimethylamino-ethylamino)-2-methyl-phenyl]-1H-pyrazolo [3,4-d] pyrimidines-4-base oxygen base }-piperidines-1-isopropyl formate (compd A 226).
To be similar to the compd A 226 (84mg, 12%) that instance 982 described modes prepare the powder that is white in color.C
25H
35N
7O
3The accurate mass calculated value be 4813, experimental value LCMS (ESI) m/z 4824 (M+H
+, 100%).
Instance 986: preparation 4-{1-{4-[(2-methylsulfonyl-ethyl)-methyl-amino]-phenyl }-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base)-piperidines-1-isopropyl formate (compd A 231).
Prepare the compd A 231 that is the beige powder to be similar to instance 982 described modes.C
24H
32N
6O
5The accurate mass calculated value of S is 516.2, experimental value LCMS (ESI) m/z 5176 (M+H
+, 78%).
Instance 987: preparation 4-{1-[4-(2-methoxyl group-ethylamino)-phenyl]-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base }-piperidines-1-isopropyl formate (compd A 232).
Prepare the compd A 232 that is the beige powder to be similar to instance 982 described modes.C
23H
30N
6O
4The accurate mass calculated value be 4542, experimental value LCMS (ESI) m/z 4555 (MH
+, 89%).
Instance 988:4-(1-{4-[(tetrahydrochysene-furans-2-ylmethyl)-amino]-phenyl }-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base)-piperidines-1-isopropyl formate (compd A 233).
Prepare the compd A 233 (5 3mg, 7%) that is yellow powder to be similar to instance 982 described modes.C
25H
32N
6O
4The accurate mass calculated value be 4802, experimental value LCMS (ESI) m/z 4816 (MH
+, 92%).
Instance 989. preparation 4-(1-{4-[4-(2-methylsulfonyl-ethyl)-piperazine-1-yl]-phenyl }-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base)-piperidines-1-isopropyl formate (compd A 234).
Prepare the compd A 234 that is brown powder to be similar to instance 982 described modes.C
27H
37N
7O
5The accurate mass calculated value of S is 571 3, experimental value LCMS (ESI) m/z 5726 (M+H
+, 74%).
Instance 990: preparation 4-[1-(4-amino-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-isopropyl formate (compd A 235).
Prepare the compd A 235 (7.3mg, 12%) that is the beige powder to be similar to instance 9.82 described modes.C
20H
24N
6O
3The accurate mass calculated value be 396, experimental value LCMS (ESI) m/z 3971 (M+H
+, 70%).
Instance 991: preparation 4-[1-(5-ethyl-pyrimidine-2-base)-piperidin-4-yl sulfenyl]-1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine (compd A 237).
Under 150 ℃ under microwave radiation with the 1-{2-fluoro-4-methylsulfonyl-phenyl in the Virahol (4mL))-4-(piperidin-4-yl sulfenyl)-1H-pyrazolo [3; 4-d] pyrimidine hydrochloride (250mg; 0.56mmol), 2-chloro-5-ethyl-pyrimidine (680 μ L; 5 6mmol) and triethylamine (315 μ L, 2 24mmol) mixture heating up 15min.Crude mixture is concentrated in a vacuum and produces the solid compd A 237 (100mg, 35%) that is white in color through the HPLC purifying.
1H?NMR(CDCl
3，400MHz)δ1?18(t，3H)，1?82-1?94(m，2H)，2?28-2.37(m，2H)，2.53(q，2H)，3?06(s，3H)，3?55-3?64(m，2H)，4?41-4?55(m，3H)，7?82(m，3H)，8?24(s，1H)，8?37(s，2H)，8?74(s，1H)。C
23H
24FN
7O
2S
2Accurate mass calculated value 513 61, experimental value 514 4 (MH
+).
Instance 992: preparation 3-tert.-butoxy-1-{4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-third-1-ketone (compound A-13 2).
Make and be solid compound A-13 2 (95%) to be similar to instance 925 described modes.
1H NMR (CDCl
3, 400MHz) δ 1.26 (d, 6H), 1 82-1 86 (m, 2H), 2 01-2.10 (m, 2H); 3.10 (s, 3H), 3 34-3 45 (m, 2H), 3 90-3 93 (m, 2H); 4 94 (nine heavy peaks, 1H), 5 44-5 48 (m, 1H), 8 09-8 12 (m, 2H); 8 26 (s, 1H), 8 60-8 62 (m, 2H), 8.67 (s, 1H).C
21H
25N
5O
5The accurate mass calculated value 459 2 of S, experimental value 460.3 (MH
+).
Instance 993: preparation (3-{4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-3-ketone group-propyl group)-methyl-t-butyl carbamate (compound A-13 3).
Make and be solid compound A-13 3 (37%) to be similar to instance 9.25 described modes.C
26H
34N
6O
6The accurate mass calculated value 558.2 of S, experimental value 559 3 (MH
+).
Instance 994: preparation { 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base is amino]-cyclohexyl }-t-butyl carbamate (compound A-13 5).
At room temperature with 4-chloro-1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3 among the THF (10mL); 4-d] pyrimidine (308mg; 1mmol), (4-amino-cyclohexyl)-t-butyl carbamate (257mg, 12mmol) and salt of wormwood (166mg, 12mmol) mixture stirred overnight.Be solid compound A-13 5 (76%) through the generation of tubing string purification by chromatography mixture.
1H?NMR(CDCl
3，400MHz)δ146(s，9H)，1?74-2?04(m，8H)，3.09(s，3H)，3.73(s，1H)，4?62(s，1H)，?8?07-8?09(m，3H)，8?49(s，1H)，8?57-8?59(m，2H)。C
23H
30N
6O
4The accurate mass calculated value 486 2 of S, experimental value 487 2 (MH
+).
Instance 9.95: preparation N-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-yl]-hexamethylene-1,4-diamines (compound A-13 6).
Make and be solid compound A-13 6 (98%) to be similar to instance 96 described modes.C
18H
22N
6O
2The accurate mass calculated value 386 2 of S, experimental value 387 1 (MH
+).
Instance 996: preparation N-{4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base is amino]-cyclohexyl }-VITAMIN PP (compd A 42).
Make and be solid compd A 42 (65%) to be similar to instance 925 described modes.C
24H
25N
7O
3The accurate mass calculated value 491 2 of S, experimental value 4923 (MH
+).
Instance 997: preparation 3-tert.-butoxy-N-{4-[1-{4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base is amino]-cyclohexyl }-propionic acid amide (compd A 43).
Make and be solid compd A 43 (24%) to be similar to instance 925 described modes.
1H?NMR(CDCl
3，400MHz)δ123(s，9H)，1?89-1.90(m，4H)，2.02-2?03(m，4H)，2?51(t，2H)，3?12(s，3H)，3?64(t，2H)，409(s，2H)，735-7?37(m，1H)，8?13(d，2H)，8?26(s，1H)，8.32(s，1H)，8?45(d，2H)，11?5-11?6(m，1H)。C
25H
34N
6O
5The accurate mass calculated value 514 2 of S, experimental value 5156 (MH
+).
Instance 998: preparation (4-{ [1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base is amino]-methyl }-cyclohexyl)-t-butyl carbamate (compd A 71).
Make and be solid compd A 71 (100%) to be similar to instance 994 described modes.
1H?NMR(CDCl
3，400MHz)δ1?35-1.85(m，19H)，3?09(s，3H)，3?61(s，2H)，3?73-3.76(m、1H)，4?64(s，1H)，8?07-8?11(m，3H)，8?50(s，1H)，8?57-8?60(m，2H)。C
24H
32N
6O
4The accurate mass calculated value 500 2 of S, experimental value 501 3 (MH
+).
Instance 999: preparation N-{4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base is amino]-cyclohexyl methyl }-VITAMIN PP (compd A 72).
Make and be solid compd A 72 (91%) to be similar to instance 925 described modes.C
25H
27N
7O
3The accurate mass calculated value 5052 of S, experimental value 5063 (MH
+).
Instance 9100: preparation N-{4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base is amino]-cyclohexyl methyl }-6-methyl-VITAMIN PP (compd A 73).
Make and be solid compd A 73 (94%) to be similar to instance 925 described modes.C
26H
29N
7O
3The accurate mass calculated value 519 2 of S, experimental value 520 5 (MH
+).
Instance 9 101: preparation 4-(2-{ ethyl-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-yl]-amino }-ethyl)-piperazine-1-t-butyl formate (compd A 101).
Prepare and be solid compd A 101 (9%) to be similar to instance 9.94 described modes.C
25H
35N
7O
4The accurate mass calculated value 529.3 of S, experimental value 530 3 (MH
+).
Instance 9102: preparation 4-({ [1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-yl]-sec.-propyl-amino }-methyl)-piperidines-1-t-butyl formate (compd A 228).
Make and be solid compd A 228 (120mg, 71%) to be similar to instance 9.94 described modes.C
26H
35FN
6O
4The accurate mass calculated value 546 2 of S, experimental value 547 7 (MH
+).
Instance 9103: preparation 4-({ [1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-yl]-sec.-propyl-amino }-methyl)-piperidines-1-isopropyl formate (compd A 236).
Prepare and be thickness buttery compd A 236 (509mg, 80%) to be similar to instance 94 described modes.C
25H
33FN
6O
4The accurate mass calculated value 532 2 of S, experimental value 533.3 (MH
+).
Instance 9104: preparation 4-[1-(2-fluoro-4-sulfamyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-isopropyl formate (compd A 239).
Step 1: preparation 3-fluoro-4-diazanyl-benzsulfamide.
Be furnished with condensing surface and N
2The stirring rod, 3 of packing in the 500mL round-bottomed flask of inlet dividing plate, 4-two fluoro-benzsulfamides (10g, 52mmol), anhydrous hydrazine (1056mL, 336mmol) and acetonitrile (180mL).At N
2Under make mixture backflow 6h.Then move down and desolventize and use H in vacuum
2O handles resistates.Filtration is through separate solid and use H
2The O washing produces the product of wanting.C
6H
8FN
3O
2The accurate mass calculated value 205 03 of S, experimental value 2061 (MH
+).
Step 2: preparation 4-[1-(2-fluoro-4-sulfamyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-isopropyl formate (compd A 239).
To be similar to instance 924 described modes, prepare compd A 239 through the HPLC purifying.
1HNMR(CDCl
3，400MHz)δ1?26(d，6H)，1.87(m，2H)，2?10(m，2H)，3?37(m，2H)，3.91(m，2H)，4?91(m，1H)，5?01(s，2H)，5?62(m，1H)，7?91(m，3H)，8?31(s，1H)，8?61(s，1H)。C
20H
23FN
6O
5The accurate mass calculated value 478 14 of S, experimental value 479.3 (MH
+).
Instance 9.105: preparation (the 1-tertiary butyl-5-methyl isophthalic acid H-pyrazoles-4-yl)-{ 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone (compd A 9).
To prepare compd A 9 with instance 9104 said identical modes.
1HNMR(CDCl
3，400MHz)δ162(s，9H)，2?01(m，2H)，2?22(m，2H)，2?47(s，3H)，3?09(s，3H)，3?65(m，1H)，3?96(m，1H)，4?23(m，1H)，4?55(m，1H)，5?72(m，1H)，6.50(s，1H)，8?10(d，2H)，8?28(s，1H)，8.62(d，2H)，8?68(s，1H)。C
26H
31N
7O
4The accurate mass calculated value 537 22 of S, experimental value 538 4 (MH
+).
Instance 9106: preparation (the 5-tertiary butyl-2-methyl-2H-pyrazole-3-yl)-{ 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone (compd A 10).
To prepare compd A 10 with instance 9104 said identical modes.
1HNMR(CDCl
3，400MHz)δ1?30(s，9H)，1?97(m，2H)，2?20(m，2H)，3.11(s，3H)，3?63(m，2H)，3.86(s，1H)，3?94(s，3H)，4.13(m，1H)，5?72(m，1H)，6.18(s，1H)，8?10(d，2H)，8.28(s，1H)，8?62(d，2H)，8.68(s，1H)。C
26H
31N
7O
4The accurate mass calculated value 537 22 of S, experimental value 538 4 (MH
+).
Instance 9107: preparation (3-fluoro-phenyl)-{ 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone (compound A-28).
In the 16mL reaction flask, packing into, (48mg is in the oil 60%, 12mmol) and 5mLTHF for sodium hydride.(66mg is 0.3mmol) also at room temperature at N in suspension-s, to add (3-fluoro-phenyl)-(4-hydroxy-piperdine-1-yl)-ketone
2In mixture is stirred 60min, then add 4-chloro-1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine (60mg, 0 2mmol).At room temperature at N
2Behind the middle restir 2h, LCMS shows that whole initial chloridization pyrazole pyrimidines transform fully.Then also produce compound A-28 through the HPLC of purifying through the injection filter filter reaction mixture.
1HNMR(CDCl
3，400MHz)δ1?95(m，2H)，2.21(m，2H)，3?11(s，3H)，3?45(m，1H)，3?68(m，1H)，3?75(m，1H)，4?20(s，1H)，5?72(m，1H)，7?12(m，1H)，7?16(m，1H)，7?22(m，1H)，7?41(m，1H)，8?11(d，2H)，8.27(s，1H)，8?62(d，2H)，867(s，1H)。C
24H
22FN
5O
4The accurate mass calculated value 495.14 of S, experimental value 4963 (MH
+).
Instance 9108. preparation 1-(2-fluoro-4-methylsulfonyl-phenyl)-4-[1-(the 3-sec.-propyl-[1,2,4] oxadiazole-5-ylmethyls)-piperidin-4-yl oxygen base]-1H-pyrazolo [3,4-d] pyrimidine (compd A 137).
To prepare compd A 137 with instance 9107 said identical modes.
1HNMR(CDCl
3，400MHz)δ1?35(d，6H)，2?06(m，2H)，2?19(m，2H)，2.60(m，2H)，2?92(m，2H)，3?13(m，2H)，3.90(s，2H)，5?47(m，1H)，7?94(m，3H)，8?32(s，1H)，8?61(s，1H)。C
23H
26FN
7O
4The accurate mass calculated value 515 18 of S, experimental value 516 4 (MH
+).
Instance 9 109: preparation 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base is amino]-piperidines-1-t-butyl formate (compd A 11).
Prepare the solid compd A 11 that is white in color to be similar to instance 994 described modes.
1HNMR(DMSO-d
6，400MHz)δ1?42(s，9H)，1?48(m，2H)，1?97(m，2H)，2.92(m，2H)，3?26(s，3H)，3?99(m，2H)，4?33(m，1H)，8?10(d，2H)，8?45(s，2H)，8.50(s，1H)，8.56(d，2H)。C
22H
28N
6O
4The accurate mass calculated value 472 19 of S, experimental value 473 4 (MH
+).
Instance 9110: preparation 3-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base is amino]-piperidines-1-t-butyl formate (compd A 24).
Prepare compd A 24 to be similar to instance 994 described modes.′H?NMR(CDCl
3，400MHz)δ140(m，2H)，1?47(s，9H)，1?66(m，1H)，1.79(m，1H)，3?09(s，3H)，3?49(m，3H)，3.79(m，1H)，4?31(m，?1H)，5?83(m，1H)，8?08(d，2H)，8?19(s，1H)，8?51(s，1H)，8?59(d，2H)。C
22H
28N
6O
4The accurate mass calculated value 472 19 of S, experimental value 473 4 (MH
+).
Instance 9111: preparation 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base is amino]-piperidines-1-isopropyl formate (compd A 12).
Step 1: preparation [1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-yl]-piperidin-4-yl-amine
In the 100mL round-bottomed flask, pack into stirring rod, compd A 11 (1g), acetonitrile (40mL) and methylene dichloride (12mL).After compound dissolution, under nitrogen, add 1, the 4M HCl in the 4-diox (12mL) also at room temperature stirs 20min with mixture.With 60% of solution concentration to initial volume.Precipitate and separate is produced [1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-yl]-piperidin-4-yl-amine.
1HNMR(DMSO-d
6，400MHz)δ1?98(m，2H)，2?11(m，2H)，3?02(m，2H)，3?26(s，3H)，3?36(m，2H)，4?44(m，1H)，8?11(d，2H)，8.47(s，1H)，8?56(d，2H)，8.79(s，1H)。C
17H
20N
6O
2The accurate mass calculated value 372 14 of S, experimental value 373 2 (MH
+).
Prepare compd A 12 to be similar to instance 94 described modes.
1HNMR(CDCl
3，400MHz)δ1.27(d，6H)，1?89(m，2H)，2?14(m，2H)，2?92(m，2H)，3?12(s，3H)，4?01(m，2H)，4?26(m，2H)，4?95(m，1H)，8?14(d，2H)，8?23(s，1H)，8?33(s，1H)，8?46(d，2H)，11?88(s，1H)。C
21H
26N
6O
4The accurate mass calculated value 458 17 of S, experimental value 459 4 (MH
+).
Instance 9 112: preparation 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base is amino]-piperidines-1-tetryl formate (compd A 13).
Prepare compd A 13 to be similar to instance 94 described modes.
1HNMR(CDCl
3，400MHz)δ0?96(d，6H)，1?57(m，2H)，1?97(m，2H)，2?22(m，2H)，3?01(m，2H)，3?12(s，3H)，3?90(d，2H)，4.25(m，2H)，4.38(m，1H)，8.09(d，2H)，8?15(s，1H)，8?49(s，1H)，8?57(d，2H)，11.88(s，1H)。C
22H
28N
6O
4The accurate mass calculated value 47219 of S, experimental value 4734 (MH
+).
Instance 9113: preparation { 3-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [34-d] pyrimidine-4-base is amino]-piperidines-1-yl }-(6-methyl-pyridin-3-yl)-ketone (compound A-45 5).
Step 1: preparation [1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-yl]-piperidines-3-base-amine.
In the 20mL round-bottomed flask, pack into stirring rod, compd A 24 (215mg) and acetonitrile (8mL).After compound dissolution, under nitrogen, add 1, the 4MHCl in the 4-diox (2mL) also at room temperature stirs 20min with mixture.With 60% of solution concentration to initial volume.Precipitate and separate is produced [1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-yl]-piperidines-3-base-amine.
1H?NMR(DMSC-d
6，400MHz)δ198(m，2H)，211(m，2H)，3?02(m，2H)，3?26(s，3H)，336(m，2H)，4?44(m，1H)，8?11(d，2H)，8?47(s，1H)，8?56(d，2H)，8?79?(s，1H)。C
17H
20N
6O
2The accurate mass calculated value 372 14 of S, experimental value 373 2 (MH
+).
Prepare compound A-45 5 to be similar to instance 925 described modes.
1HNMR(DMSO-d
6，400MHz)δ1.67(m，1H)，1?77(m，1H)，1?97(m，1H)，2.11(m，1H)，2?55(s，3H)，3?20(m，1H)，3?26(s，3H)，3?50(m，1H)，3?80(m，1H)，4?05(m，1H)，4?19(m，1H)，434(m，1H)，4.61(m，1H)，7.53(m，1H)，8?05(m，1H)，8?11(d，2H)，8?32(m，1H)，8?41(m，1H)，8?55(m，2H)，8.64(m，1H)。C
24H
25N
7O
3The accurate mass calculated value 491 17 of S, experimental value 492 3 (MH
+).
Instance 9.114: preparation { 3-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base is amino]-piperidines-1-yl }-(2-methyl-pyridin-3-yl)-ketone (compound A-45 6).
Prepare compound A-45 6 to be similar to instance 925 described modes.
1HNMR(DMSO-d
6，400MHz)δ170(m，1H)，1?77(m，1H)，1?97(m，1H)，2?11(m，1H)，2?33(m，1H)，2?55(m，1H)，3?10(m，2H)，3?26(s，3H)，3?50(m，1H)，4?05(m，1H)，4.10(m，1H)，4?34(m，1H)，4.56(m，1H)，7?53(m，1H)，8?11(d，2H)，8?13(m，1H)，8?40(m，1H)，8?51(m，1H)，8?55(m，2H)，8?57(m，2H)。C
24H
25N
7O
3The accurate mass calculated value 491.17 of S, experimental value 492 3 (MH
+).
Instance 9115: preparation { 3-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base is amino]-piperidines-1-yl }-(5-methyl-pyridin-3-yl)-ketone (compound A-45 7).
Prepare compound A-45 7 to be similar to instance 925 described modes.
1H?NMR(DMSO-d
6，400MHz)δ1?67(m，1H)，1?80(m，1H)，1?97(m，1H)，2?09(m，1H)，2?33(m，1H)，2?40(m，1H)，2?69(m，2H)，3.26(s，3H)，3?40(m，1H)，3?70(m，1H)，4?17(m，2H)，4?10(m，1H)，4.34(m，1H)，4?56(m，1H)，7.64(m，1H)，8?11(d，2H)，8?20(m，1H)，8?35(m，1H)，8?45(m，1H)，8.55(m，2H)，8?57(m，2H)。C
24H
25N
7O
3The accurate mass calculated value 491 17 of S, experimental value 492.3 (MH
+).
Instance 9.116: preparation { 3-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base is amino]-piperidines-1-yl }-pyridin-3-yl-ketone (compound A-45 8).
Prepare compound A-45 8 to be similar to instance 925 described modes.
1H?NMR(DMSO-d
6，400MHz)δ1?67(m，1H)，1?80(m，1H)，1.97(m，1H)，2?09(m，1H)，2?33(m，1H)，2?40(m，1H)，2?69(m，2H)，3?26(s，3H)，3?40(m，1H)，3.70(m，1H)，4?17(m，2H)，4?10(m，1H)，4?34(m，1H)，4?56(m，1H)，7.64(m，1H)，8?11(d，2H)，8?20(m，1H)，8.35(m，1H)，8?45(m，1H)，8?55(m，2H)，8?57(m，2H)。C
23H
23N
7O
3The accurate mass calculated value 477 16 of S, experimental value 478 3 (MH
+).
Instance 9117: preparation { 3-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base is amino]-piperidines-1-yl }-(1-methyl isophthalic acid H-pyrroles-3-yl)-ketone (compound A-45 9).
Prepare compound A-45 9 to be similar to instance 925 described modes.
1HNMR(DMSO-d
6，400MHz)δ1?60(m，?1H)，1.69(m，1H)，1?87(m，1H)，2?11(m，1H)，269(m，2H)，3.11(m，2H)，3?26(s，3H)，3?62(s，3H)，4?10(m，1H)，4?20(m，1H)，4?39(m，1H)，6?01(m，1H)，6?49(m，1H)，6?83(s，1H)，8?11(d，2H)，8?46(s，1H)，8.48(s，1H)，8.35(m，1H)，8.56(d，2H)，8?57(s，1H)。C
23H
25N
7O
3The accurate mass calculated value 479 17 of S, experimental value 480 3 (MH
+).
Instance 9118: preparation { 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-(4-trifluoromethyl-pyridin-3-yl)-ketone (compd A 62).
Prepare compd A 62 to be similar to instance 925 described modes.
1H?NMR(DMSO-d
6，400MHz)δ1?86(m，1H)，1?90(m，1H)，2?08(m，1H)，2?20(m，1H)，3?28(s，3H)，3?60(m，1H)，3?69(m，1H)，4?04(m，1H)，4?13(m，1H)，5?71(m，1H)，7.89(d，1H)，8?15(d，2H)，S18(m，1H)，8?56(d，2H)，8?71(s，1H)，8?80(s，1H)，8?85(m，1H)，8?93(m，1H)。C
24H
21F
3N
6O
4S accurate mass calculated value 546 13, experimental value 547 2 (MH
+).
Instance 9 119: preparation (the 6-tertiary butyl-pyridin-3-yl)-{ 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone (compd A 70).
Step 1: the preparation 6-tertiary butyl-cigarette nitrile.
Is furnished with N to exsiccant in baking box
2Pack in the 500mL round-bottomed flask of inlet and be dissolved in the anhydrous Et of 100mL fully
2In the 3-cyanopyridine (2g) among the O.At N
2In above-mentioned solution, dropwise add the 17Mt-BuLi in the pentane down with syringe.In about 30min, accomplish and drip.At room temperature at N
2In the gained mixture is stirred 20h.Then mixture is cooled off 20min in ice bath.Dropwise add icy water (300mL).Removing sap green suspension-s and solution becomes gets little faint yellow.Use EtOAc/H
2The O extraction solution.Organic extract is concentrated, through silicone tube column chromatography (15%EtOAc/ hexane) with its purifying.
1H?NMR(CDCl
3，400MHz)δ1?38(s，9H)，7?46(d，1H)，7?88(m，1H)，8?82(s，1H)。C
10H
12N
2Accurate mass calculated value 160.10, experimental value 161 2 (MH
+).
Step 2: the preparation 6-tertiary butyl-nicotinic acid.
The 6-tertiary butyl-cigarette nitrile (160mg) and the dense HCl of 15mL pack in the 5mL reaction flask.Under 80 ℃, reaction mixture is heated overnight.Concentrate the gained mixture in a vacuum.Through HPLC purifying resistates.
1HNMR(CDCl
3，400MHz)δ1?49(s，9H)，7?81(d，1H)，8?76(m，1H)，9.48(s，1H)。C
10H
13NO
2Accurate mass calculated value 179 09, experimental value 180 2 (MH
+).
Step 3: preparation (the 6-tertiary butyl-pyridin-3-yl)-{ 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone (compd A 70).
Stirring rod, 4-tertiary butyl nicotinic acid (30mg), phosphofluoric acid O-(7-azepine benzo triazol-1-yl)-N, N, N ', N '-tetramethyl-urea (60mg) and DMF (1mL) pack in the 20mL reaction flask.At room temperature at N
2Down mixture is stirred 10min.Add 1-(4-methylsulfonyl-phenyl)-4-(piperidin-4-yl oxygen base)-1H-pyrazolo [3,4-d] pyrimidine (17 2mg) and triethylamine (100 μ l).At room temperature at N
2Under stir and make behind the 3H reaction mixture pass through injection filter to filter.To filtrate concentrate and through HPLC with its purifying.
1HNMR(DMSO-d
6，400MHz)δ1?34(s，9H)，1?88(m，2H)，2?14(m，2H)，3?28(s，3H)，3?62(m，3H)，4?06(m，1H)，5?72(m，1H)，7?53(d，1H)，7.84(m，1H)，8?15(d，2H)，8?18(m，1H)，8.55(d，2H)，8.60(m，1H)，8.66(s，1H)，8?81(s，1H)。C
27H
30N
6O
4The accurate mass calculated value 534 20 of S, experimental value 535 4 (MH
+).
Instance 9.120: preparation 4-{ [1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base is amino]-methyl }-piperidines-1-t-butyl formate (compd A 76).
To prepare compd A 76 with instance 9.94 said identical modes.
1HNMR(CDCl
3，400MHz)δ1?41(s，9H)，1?77(m，2H)，1?86(m，1H)，2?69(m，2H)，3?07(s，3H)，3?54(m，3H)，4?12(m，2H)，6.44(m，1H)，8?03(d，2H)，8?16(s，1H)，8?45(s，1H)，8?55(d，2H)。C
23H
30N
6O
4The accurate mass calculated value 486 20 of S, experimental value 487 4 (MH
+).
Instance 9121: preparation 4-({ [1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-yl]-methyl-amino }-methyl)-piperidines-1-t-butyl formate (compd A 75).
Step 1: preparation 4-methyl carbamyl-piperidines-1-t-butyl formate.
At the 1-tert-butoxycarbonyl in THF (32mL) under 0 ℃-different piperidine carboxylic acid (10g) and Et
3N (592mL) dropwise adds isobutyl chlorocarbonate (566mL) through stirred solution.Under 0 ℃, before with THF (120mL) dilution, the gained mixture is stirred 30min and adds 2M methylamine (80mL).At room temperature with the reaction mixture stirred overnight.Remove excessive THF in a vacuum.Resistates is dissolved in water and extracts with EtOAc.Use 1N NaOH, then use the brine wash organic extract.Through Na
2SO
4After the drying, it is concentrated produce crude product.
The stirring rod of in the 32mL reaction flask, packing into be dissolved in the 4-methyl carbamyl-piperidines-1-t-butyl formate (0 97g) among the anhydrous THF of 12.8mL.With ice bath solution is cooled to 0 ℃.65% toluene solution that under 0 ℃, dropwise adds Red-Al (3 66mL).After being added dropwise to complete, at room temperature at N
2Under stir the mixture until the lucky completely consumed of all raw materials.Under 0 ℃, reaction mixture is dissolved in H
2Among the O, extract with EtOAc (x3).With saturated NaCl solution washing EtOAc extract.Through Na
2SO
4After the drying, organic layer is concentrated generation 550mg crude product.
Step 3: preparation 4-({ [1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-yl]-methyl-amino }-methyl)-piperidines-1-t-butyl formate (compd A 75).
Use 4-chloro-1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine and methylamino-methyl-piperidines-1-t-butyl formate and prepare compd A 75 to be similar to 994 described modes through preparation type thin layer chromatography purifying.
1HNMR(CDCl
3，400MHz)δ1?27(m，2H)，1?44(s，9H)，1?63(m，2H)，2?03(m，1H)，2.69(m，2H)，3?09(s，3H)，3?49(s，3H)，4?12(m，2H)，8?08(d，2H)，8?18(s，1H)，8?49(s，1H)，8?57(d，2H)。C
24H
32N
6O
4The accurate mass calculated value 500.22 of S, experimental value 501.4 (MH
+).
Instance 9122: preparation 3-{ [1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [34-d] pyrimidine-4-base is amino]-methyl }-piperidines-1-t-butyl formate (compd A 77).
To be similar to instance 994 described modes and to prepare compd A 77 through the preparation type thin layer chromatography purifying that uses the 50%EtOAc/ hexane.
1HNMR(CDCl
3，400MHz)δ1?44(s，9H)，1?83(m，2H)，1.91(m，2H)，2?73(m，2H)，3.10(s，3H)，3.59(s，3H)，4?13(m，2H)，8?08(d，2H)，8?15(s，1H)，8?49(s，1H)，8?57(d，2H)。C
23H
30N
6O
4The accurate mass calculated value 486 20 of S, experimental value 487 4 (MH
+).
Instance 9123: preparation 4-({ [1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-yl]-sec.-propyl-amino }-methyl)--piperidines-1-isopropyl formate (compd A 236).
Prepare and be thickness buttery compd A 236 (509mg, 80%) to be similar to instance 9121 described modes.C
25H
33FN
6O
4The accurate mass calculated value 532 2 of S, experimental value 533 3 (MH
+).
Instance 9124: preparation 4-(ethyl-[1-{4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-yl]-amino }-methyl)-piperidines-1-t-butyl formate (compd A 78).
Step 1: preparation 4-(acetamido-methyl)-piperidines-1-t-butyl formate.
The stirring rod of in the 32mL reaction flask, packing into be dissolved in the Et among the anhydrous THF of 10mL
3N (05mL) and 4-amino methyl-piperidines-1-t-butyl formate (13g).Under 0 ℃, dropwise add Mono Chloro Acetic Acid (0 48g) through injection.At room temperature mixture is stirred 2h.Under 0 ℃, be dissolved in H
2With EtOAc it is extracted behind the O.With 2M NaOH solution, NaHSO
4With saturated NaCl solution washing organic extract.With it through Na
2SO
4It is concentrated produce thick 4-(ethanamide-methyl)-piperidines-1-t-butyl formate.
1HNMR(CDCl
3，400MHz)δ1?14(m，2H)，1.45(s，9H)，1?65(m，2H)，1?68(m，1H)，1?99(s，3H)，2?66(m，2H)，3?14(m，2H)，4?12(m，2H)，5?51(m，1H)。C
13H
24N
2O
3Accurate mass calculated value 256 18, experimental value 257 4 (MH
+).
Step 2: preparation 4-ethylamino methyl-piperidines-1-t-butyl formate.
Prepare 4-ethylamino methyl-piperidines-1-t-butyl formate to be similar to instance 9121 described modes.
1H?NMR(CDCl
3，400MHz)δ1?11(m，3H)，1?26(m，2H)，1?45(s，9H)，1.64(m，1H)，1?71(m，2H)，2?50(m，2H)，2?65(m，4H)，4.12(m，2H)。C
13H
26N
2O
2Accurate mass calculated value 242.20, experimental value 243 4 (MH
+).
Step 3: preparation 4-(ethyl-[1-{4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-yl]-amino }-methyl)-piperidines-1-t-butyl formate (compd A 78).
Prepare compd A 78 to be similar to instance 9121 described modes.
1H?NMR(CDCl
3，400MHZ)δ1?26(m，3H)，1.36(m，2H)，1?40(s，9H)，1?63(m，2H)，2?03(m，1H)，2?69(m，2H)，3?09(s，3H)，3?68(m，2H)，3?82(m，2H)，4.12(m，2H)，8?08(d，2H)，8?09(s，1H)，8?46(s，1H)，8?57(d，2H)。C
25H
34N
6O
4The accurate mass calculated value 514 24 of S, experimental value 515 4 (MH
+).
Instance 9125 preparation 4-({ ethyl-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-yl]-amino }-methyl)-piperidines-1-t-butyl formates (compound A-28 8).
Prepare compound A-28 8 to be similar to instance 9.121 described modes.
1H?NMR(CDCl
3，400MHz)δ1?26(m，3H)，1?36(m，2H)，1?40(s，9H)，1.63(m，2H)，2?03(m，1H)，2?69(m，2H)，3?09(s，3H)，3?68(m，2H)，3?82(m，2H)，4?12(m，2H)，7?90(m，1H)，7?93(m，1H)，7?96(m，1H)，8?12(s，1H)，8?41(s，1H)。C
25H
33FN
6O
4The accurate mass calculated value 532 23 of S, experimental value 533 4 (MH
+).
Instance 9126: preparation 4-{1-[2-(2-dimethylamino-oxyethyl group)-4-methylsulfonyl-phenyl]-1H-pyrazolo [3,4-d]-pyrimidine-4-base oxygen base }-piperidines-1-t-butyl formate (compd A 79).
Step 1: preparation 1-[2-(2-dimethylamino-oxyethyl group)-4-methylsulfonyl-phenyl]-1H-pyrazolo [3,4-d] pyrimidine-4-alcohol.
The stirring rod of in reaction flask, packing into and NaH are (in the oil 60%, 90mg).Dimethylaminoethanol (200mg) is dissolved in diox (1.5mL) and at N
2Down it is added reaction flask.At room temperature, mixture is stirred 1h adding 1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-alcohol (50mg) is preceding.Under 70 ℃, reaction mixture was heated 60 hours.Reaction soln is concentrated in a vacuum and pure through preparation HPLC purifying 1-[2-(2-dimethylamino-oxyethyl group)-4-methylsulfonyl-phenyl]-1H-pyrazolo [3,4-d] pyrimidine-4-.
1HNMR(DMSO-d
6，400MHz)δ2.68(s，6H)，3?36(s，3H)，3?40(m，2H)，4?54(m，2H)，7?74(m，1H)，7.78(m，1H)，7?85(m，1H)，8.10(s，1H)，8?37(s，1H)，9.75(s，1H)，12?5(s，1H)。C
16H
19N
5O
4The accurate mass calculated value 377 12 of S, experimental value 377 9 (MH
+).
Stirring rod, 1-[2-(2-dimethylamino-oxyethyl group)-4-methylsulfonyl-phenyl]-1H-pyrazolo [3,4-d] pyrimidine-4-alcohol (50mg), POCl pack in reaction flask
3(0 5mL) and N, accelerine (15 μ l).Under 100 ℃, reaction mixture is stirred 1h., reaction mixture forms white precipitate when being cooled to room temperature.At room temperature the mixture sealing was preserved weekend.After concentrating in a vacuum, use Et
2O debris and filtration produce solid { 2-[2-(4-chloro-pyrazolo [34-d] pyrimidine-1-yl)-5-methylsulfonyl-phenoxy]-ethyl }-dimethyl--amine that is white in color.C
16H
18ClN
5O
3The accurate mass calculated value 395 08 of S, experimental value 396 (MH
+).
Step 3: preparation 4-{1-[2-(2-dimethylamino-oxyethyl group)-4-methylsulfonyl-phenyl]-1H-pyrazolo [3,4-d]-pyrimidine-4-base oxygen base }-piperidines-1-t-butyl formate (compd A 79).
Stirring rod, NaH in reaction flask, pack into (in the oil 60%, 110mg), 4-hydroxy-piperdine-1-t-butyl formate (70mg) and THF (3mL).At room temperature at N
2Down mixture is stirred 15min.Then add { 2-[2-(4-chloro-pyrazolo [3,4-d] pyrimidine-1-yl)-5-methylsulfonyl-phenoxy]-ethyl }-dimethyl--amine.Under 80 ℃, mixture is stirred 30min.After being cooled to room temperature, use H
2The O stopped reaction is also used CH
2Cl
2Extraction product.Concentrate organic extract in a vacuum.Through with 20%MeOH/CH
2Cl
2Silicone tube column chromatography purification as scrub solution produces 4-{1-[2-(2-dimethylamino-oxyethyl group)-4-methylsulfonyl-phenyl]-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base }-piperidines-1-t-butyl formate.
1H?NMR(CDCl
3，400MHz)δ?1?49(s，9H)，1?88(m，2H)，2?10(m，2H)，2?20(s，6H)，2?67(t，2H)，3?10(s，3H)，3?32(m，2H)，3?87(m，2H)，4?28(t，2H)，5?59(m，1H)，7?70(m，3H)，8?25(s，1H)，8?54(s，1H)。C
26H
36N
6O
6The accurate mass calculated value 560 24 of S, experimental value 561.4 (MH
+).
Instance 9127: preparation 4-((2-dimethylamino-ethyl)-[1-(the 4-methylsulfonyl]-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-yl]-amino }-methyl)-piperidines-1-t-butyl formate (compd A 98).
Step 1: preparation 4-(2-dimethylamino-ethyl carbamyl)-piperidines-1-t-butyl formate.
By 1-tert-butoxycarbonyl-different piperidine carboxylic acid (5g), isobutyl chlorocarbonate (283mL) and N, N-dimethyl--1 (263mL) preparation 4-(2-dimethylamino-ethyl carbamyl)-piperidines-1-t-butyl formate.C
15H
29N
3O
3Accurate mass calculated value 29922, experimental value 300.4 (MH
+).
Step 2: preparation 4-[(2-dimethylamino-ethylamino)-methyl]-piperidines-1-t-butyl formate.
Prepare 4-[(2-dimethylamino-ethylamino)-methyl]-piperidines-1-t-butyl formate to be similar to instance 9121 described modes.C
15H
31N
3O
2Accurate mass calculated value 28524, experimental value 2864 (MH
+).
Step 3: preparation 4-((2-dimethylamino-ethyl)-[1-(the 4-methylsulfonyl]-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-yl]-amino }-methyl)-piperidines-1-t-butyl formate (compd A 98).
Prepare compd A 98 to be similar to instance 9121 described modes.
1H?NMR(CDCl
3，400MHz)δ1?28(m，2H)、1?46(s，9H)，1?72(m，2H)，2?04(m，4H)，2?66(m，2H)，3?01(s，6H)，3?10(s，3H)，3?44(m，2H)，3.68(m，2H)，4?22(m，2H)，8?05(s，1H)，8?08(d，2H)，8.47(s，1H)，8?53(d，2H)，12?0(s，1H)。C
27H
39N
7O
4The accurate mass calculated value 557 28 of S, experimental value 558 4 (MH
+).
Instance 9.128: preparation 4-({ (2-dimethylamino-ethyl)-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-yl]-amino }-methyl)-piperidines-1-t-butyl formate (compd A 99).
Prepare compd A 99 to be similar to instance 9127 described modes.
1H?NMR(CDCl
3，400MHz)δ1?28(m，2H)，1?47(s，9H)，1?72(m，2H)，2?04(m，2H)，2.66(m，2H)，3?01(s，6H)，3.13(s，3H)，3?46(m，2H)，3?69(m，2H)，4?22(m，4H)，8?05(s，1H)，7?88(m，1H)，7 91(m，1H)，7?94(m，1H)，8.11(s，1H)，8?44(s，1H)，12?0(s，1H)。C
27H
38FN
7O
4The accurate mass calculated value 575 27 of S, experimental value 576 4 (MH
+).
Instance 9129: preparation { 4-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-(4-trifluoromethoxy-phenyl)-ketone (compd A 189).
In the 50mL round-bottomed flask, pack into 1-(2-fluoro-4-methylsulfonyl-phenyl)-4-(piperidin-4-yl oxygen base)-1H-pyrazolo [3,4-d] pyrimidine (300mg, 0 7mmol) and triethylamine (584 μ l).Add DMF (6mL) with complete dissolved solids material.Reaction flask is immersed in the ice bath.With trifluoromethoxy Benzoyl chloride 99min. (180mg, 0 8mmol) add solution and under 0 ℃ at N
2Down mixture is stirred 2h.After LCMS showed that all initial amine transform fully, water was ended said reaction.Then reaction mixture is concentrated and purifying in preparation HPLC in a vacuum.
1H?NMR(CDCl
3，400MHz)δ1?98(m，1H)，?2?12(m，2H)，2?27(m，1H)，3.13(s，3H)，3?51(m，1H)，3.79(m，2H)，4?21(m，1H)，5.76(m，1H)，7?31(d，2H)，7?52(d，2H)，7?95(m，3H)，836(s，1H)，8.65(s，1H)。C
25H
21F
4N
5O
5The accurate mass calculated value 579 12 of S, experimental value 580.2 (MH
+).
Instance 9130: preparation { 4-[1-(3,5-couple-trifluoromethyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base is amino]-cyclohexyl }-t-butyl carbamate (compd A 44).
With 1-(3; 5-pair-trifluoromethyl-phenyl)-4-chloro-1H-pyrazolo [3; 4-d] pyrimidine (147mg; 0 4mmol), (4-amino-cyclohexyl)-t-butyl carbamate (0 44mmol, 1.1 equivalents) and diisopropylethylamine (0.44mmol, 11 equivalents) are dissolved among the THF (3mL) and then with its stirred overnight at room temperature.Remove THF in a vacuum and solid residue is dissolved in 30/70 mixture of water and CAN again and produce yellow solid.The water wash solids also is dried the compd A 44 (179mg, 82%) that generation is the butteriness green solid in a vacuum
1H NMR (CDCl
3, 400MHz) δ 1 43 (s, 9H), 1.75 (m, 2H), 1 98-1 97 (m, 2H), 2 04 (m, 2H), 2.95 (sb, 2H), 412 (q, 1H), 4.62 (m, 1H), 7 80 (s, 1H), 8 09 (s, 1H), 8.50 (s, 1H), 8 94 (s, 2H).C
24H
26F
6N
6O
2Accurate mass calculated value 544 2, experimental value 545 5 (MH
+).
Instance 9131: preparation 4-[1-(3,5-couple-trifluoromethyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-t-butyl formate (compd A 46).
With 1-(3,5-couple-trifluoromethyl-phenyl)-4-chloro-1H-pyrazolo [3,4-d] pyrimidine (73mg; 0 2mmol); 4-hydroxy-piperdine-1-t-butyl formate (0 3mmol, 15 equivalents) and NaH (1 2mmol, 6 equivalents) are dissolved among the THF (3mL) and then with its stirred overnight at room temperature.Remove the THF solvent in a vacuum and the oily solid residue is dissolved in the water and produces with ethyl acetate extraction and be yellow-green colour buttery compd A 46 (111mg, 90%).
1HNMR(CDCl
3，400MHz)δ1?48(s，9H)，1?88-1.84(m，2H)，2?09(m，2H)，3?35-3?29(m，2H)，3?87-3?80(m，2H)，5?62-5?59(m，1H)，7.81(s，1H)，8?26(s，1H)，8?69(s，1H)，8?96(s，2H)。C
23H
23F
6N
5O
3Accurate mass calculated value 531.17, experimental value 532 2 (MH
+).
Instance 9132: preparation 4-[1-(4-(2-methylsulfonyl-ethyl)-phenyl]-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-carboxylic acid tert-butyl ester (compd A 45)
Make the compd A 45 (75mg, 100%) that is the butteriness yellow solid to be similar to instance 91 described modes.
1HNMR(CDCl
3，400MHz)δ1.50(s，9H)，1?87-1?85(m，2H)，2?11-2?09(m，2H)，2?88(s，3H)，3?28-3.23(m，2H)，3?36-3?31(m，4H)，3?88(m，2H)，5.62-5?59(m，1H)，7.41(d，2H)，8?18(d，2H)，8?21(s，1H)，8.62(s，1H)。C
24H
31N
5O
5The accurate mass calculated value 501 2 of S, experimental value 502.3 (MH
+).
Instance 9133: preparation 4-[1-(3-fluoro-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-t-butyl formate (compound A-45 0)
Make the compound A-45 0 (86mg, 100%) that is yellow solid to be similar to instance 91 described modes.
1H?NMR(CDCl
3，400MHz)51.49(s，9H)，1?89-1?84(m，2H)，2?09(m，2H)，3?36-3?29(m，2H)，3?85(m，?2H)，5?59(m，1H)，7?07-7.03(m，1H)，7?52-7?46(m，1H)，8?08(t，2H)，8?21(s，1H)，8?64(s，1H)。C
21H
24FN
5O
3Accurate mass calculated value 413 19, experimental value 414 4 (MH
+).
Instance 9.134: preparation { 4-[1-(3-fluoro-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base is amino]-cyclohexyl }-t-butyl carbamate (compound A-45 3).
To be similar to the instance 9130 described modes solid compound A-45 3 (108mg, 100%) that obtains to be white in color.
1HNMR(CDCl
3，400MHz)δ147(s，9H)，1.93-1?85(m，4H)，2?00-1.97(m，4H)，3?79(sb，1H)，4?02(sb，NH)，4?85(sb，1H)，7?14(t1H)，7?52(tt，1H)，7?90(d，1H)，7?95(d，1H)，8?19(s，1H)，8?26(s，1H)，11?5(s，NH)。C
22H
27FN
6O
2Accurate mass calculated value 426 22, experimental value 427.4 (MH
+).
Instance 9135: preparation { 4-[1-(2,4-two fluoro-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base is amino]-cyclohexyl }-t-butyl carbamate (compound A-45 2).
Make the solid compound A-45 2 that is white in color (63mg, 71%) to be similar to instance 9130 described modes.
1HNMR(CDCl
3，400MHz)δ1.47(s，9H)，1?93-1?87(m，4H)，2?01-1?98(m，4H)，3?79(sb，1H)，4?03(sb，1H)，4?88(sb，1H)，7?10(t，2H)，7.59-7?53(m，1H)，8?20(s，1H)，8?23(s，1H)，11?5(s，1H。C
22H
26F
2N
6O
2Accurate mass calculated value 444.2, experimental value 445 5 (MH
+).
Instance 9136: preparation 4-[1-(2,4-two fluoro-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-t-butyl formate (compound A-45 1).
Make the solid compound A-45 1 that is white in color (89mg, 99%) to be similar to instance 9131 described modes.
1HNMR(CDCl
3，400MHz)δ1?49(s，9H)，1.88-1?84(m，2H)，2?09(m，2H)，3?36-3?30(m，2H)，3?86(m，2H)，5?60-5?58(m，1H)，7.10-7?05(m，2H)，7?61(m，1H)，8?26(s，1H)，8?58(s，1H)。C
21H
23F
2N
5O
3Accurate mass calculated value 431 2, experimental value 432 2 (MH
+).
Instance 9137: preparation N-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-yl]-hexamethylene-1,4-diamines (compound A-45 4).
{ 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base is amino]-cyclohexyl }-t-butyl carbamate (30mg, 0 06mmol) is dissolved among the 4M HCl in the diox (2mL), follows under 40 ℃ its stirred overnight.Evaporation gained solution produces the solid compound A-45 4 (24mg, 100%) that is white in color.C
18H
22N
6O
2The accurate mass calculated value 386 2 of S, experimental value 387.2 (MH
+).
Instance 9138: preparation { 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-cyclohexyl }-t-butyl carbamate (compd A 60).
Make the solid compd A 60 that is white in color (45mg, 46%) to be similar to instance 9131 described modes.
1HNMR(CDCl
3，400MHz)δ1?21-1?12(m，2H)，1?44(s，9H)，1?72-1?67(m，2H)，2?14(db，2H)，2?25(db，2H)，3.10(s，3H)，3?46-3?42(m，1H)，4?47(sb，1H)，5?38-5?33(m，1H)，8?10(d，2H)，8.25(s，1H)，8?60?(d，2H)，865(s，1H)。C
23H
29N
5O
5The accurate mass calculated value 487 2 of S, experimental value 488 4 (MH
+).
Instance 9139: preparation N-[1-(2,4-two fluoro-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-yl]-hexamethylene-1,4-diamines (compd A 61).
The protection method of generally going according in the instance 96 obtains to be the compd A 61 (11mg, 100%) of yellow solid.C
17H
18F
2N
6Accurate mass calculated value 344 2, experimental value 345 2 (MH
+).
Instance 9140: preparation 4-[1-(2,5-two fluoro-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-t-butyl formate (compound A-28 6).
Make the solid compound A-28 6 that is white in color (29mg, 45%) to be similar to instance 9131 described modes.
1HNMR(CDCl
3，400MHz)δ1?49(s，9H)，1?89-1?84(m，2H)，2?12-2?07(m，2H)，336-3?29(m，2H)，3.89-3.58(m，2H)，5?60-5?58(m，1H)，7?19-7?17(m，1H)，7?31-7?28(m，1H)，7?43-7?39(m，1H)，8.27(s，1H)，8?60(s，1H)。C
21H
23F
2N
5O
3Accurate mass calculated value 431 18, experimental value 432 3 (MH
+).
Instance 9141: preparation 4-[({ 1-[4-(2-methylsulfonyl-ethyl)-phenyl]-1H-pyrazolo [3,4-d] pyrimidine-4-yl }-methyl-amino)-methyl]-piperidines-1-t-butyl formate (compd A 92).
Make the compd A 92 (33mg, 42%) that is yellow solid to be similar to instance 994 described modes.
1H?NMR(CDCl
3，400MHz)δ1?33-1?28(m，2H)，1?47(s，9H)，1?73(m，1H)，2?07(m，1H)，2?81(m，2H)，2?90(s，3H)，3?27-3?23(m，2H)，3?36-3?33(m，2H)，3?50(sb，3H)，3?79(m，2H)，4?15(m，2H)，7?41(d，2H)，8?13-1?11(m，3H)，8.50(sb，1H)。C
26H
36N
6O
4The accurate mass calculated value 528 2 of S, experimental value 529 3 (MH
+).
Instance 9 142: preparation 4-({ [1-(2,5-two fluoro-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-yl]-methyl-amino }-methyl)-piperidines-1-t-butyl formate (compd A 93).
Make the compd A 93 (7mg, 10%) that is yellow solid to be similar to instance 994 described modes.
1H?NMR(CDCl
3，400MHz)δ1?30(m，2H)，1?46(s，9H)，1?72(m，2H)，2?11-2?07(m，1H)，2?71(m，2H)，3?58(s，3H)，3?81(m，2H)，4?15(m，2H)，7?24-7?20(m，1H)，7?36-7?27(m，2H)，8?28(s，1H)，8?51(s，1H)。C
23H
28F
2N
6O
2Accurate mass calculated value 458 2, experimental value 459 4 (MH
+).
Instance 9143: preparation 4-[1-(2-methyl-4-third amino-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-isopropyl formate (compd A 215).
With 4-[1-(4-iodo-2-methyl-phenyl)-1H-pyrazolo [3; 4-d] pyrimidine-4-base oxygen base]-piperidines-1-isopropyl formate (78mg; 0 15mmol), propylamine (0 75mmol, 5 equivalents), proline(Pro) (0 27mol, 18 equivalents), cupric iodide (0 15mmol; 1 equivalent) and salt of wormwood (0 15mmol, 1 equivalent) is dissolved among the DMSO (2mL) and under 100 ℃, in microwave, it is stirred 30min.Produce the solid compd A 215 (36mg, 53%) that is white in color through preparation type TLC (isohexane ethyl acetate=1 1, Rf=0 7) purifying crude product.
1H NMR 400MHz CDCl
3δ (ppm): 8 51 (s, 1H); 8.20 (s, 1H), 7 40-736 (m, 1H), 7 30-7 21 (m, 2H), 5 63-5.58 (m, 1H); 4 95 (nine heavy peaks, 1H), 3 89 (m, 2H), 3 41-3 35 (m, 2H), 3 23-3.19 (m, 2H); 2 16-2 03 (m, 4H), 1 89-1 86 (m, 2H), 1.27 (d, 6H), 1 04 (t, 2H).C
24H
32N
6O
3The accurate mass calculated value be 452.2, experimental value LCMS (ESI) m/z 4534 (M+H
+, 100%).
Instance 9144: preparation 4-[1-(4-isopropylamino-2-methyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-isopropyl formate (compd A 216).
Make the compd A 216 (25mg, 38%) that is yellow oily to be similar to instance 9143 described modes.
1HNMR (CDCl
3, 400MHz) δ 1.28 (d, 6H), 1 42 (d, 6H), 1 93-1.88 (m, 2H), 2.14-2.11 (m; 2H), 2 21 (s, 3H), 3 44-3 37 (m, 2H), 3 69 (nine heavy peaks, 1H); 3 93-3 89 (m, 2H), 4.96 (nine heavy peaks, 1H), 5 63 (m, 1H), 7 50 (s; 2H), 7 54 (s, 1H), 8 24 (s, 1H), 8.57 (s, 1H).C
24H
32N
6O
3Accurate mass calculated value 452 2, experimental value 453.4 (MH
+).
Instance 9145: preparation 4-[1-(2-methyl-4-morpholine-4-base-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-isopropyl formate (compd A 217).
Make the compd A 217 (47mg, 65%) that is yellow oily to be similar to instance 9143 described modes.
1HNMR (CDCl
3, 400MHz) δ 1.28 (d, 6H), 1 94-1 89 (m, 2H), 2 15-2 09 (m, 2H), 2 19 (s; 3H), and 3.45-3 39 (m, 2H), 3 53-3 50 (m.4H), 3 94-3 88 (m, 2H), 4 12-4.10 (m, 4H); 4 96 (nine heavy peaks, 1H), 5 64 (m, 1H), 7 35 (d, 1H), 7 42 (s; 1H), 7.47 (d, 1H), 8 29 (s, 1H), 8 59 (s, 1H).C
25H
32N
6O
4Accurate mass calculated value 480 3, experimental value 481 4 (MH
+).
Instance 9.146: preparation 4-{1-[4-(2-methoxyl group-ethylamino)-2-methyl-phenyl]-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base }-piperidines-1-isopropyl formate (compd A 218).
Make the compd A 218 (25mg, 36%) that is yellow oily to be similar to instance 9143 described modes.
1HNMR (CDCl
3, 400MHz) δ 1 27 (d, 6H), 1 90-1 86 (m, 2H), 2 12-2 03 (m, 2H); 2 12 (s, 3H), 3 40 (s, 3H), 3 45-3 35 (m, 4H), 3 71-3.66 (m; 2H), 3 90 (m, 2H), 4 95 (nine heavy peaks, 1H), 5 62-5 59 (m, 1H); 7 10 (sb, 2H), 7 33 (d, 1H), 8 20 (s, 1H).C
24H
32N
6O
4Accurate mass calculated value 468 3, experimental value 469.4 (MH
+).
Instance 9147: preparation 4-(1-{4-[(2-methylsulfonyl-ethyl)-methyl-amino]-2-methyl-phenyl }-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base)-piperidines-1-isopropyl formate (compd A 219).
To be similar to the compd A 219 (6mg, 75%) that instance 9.143 described modes make the gummy solid that is white in color.C
25H
34N
6O
5The accurate mass calculated value 530 2 of S, experimental value 531 5 (MH
+).
Instance 9.148: preparation (2-{4-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-5-methyl-pyrimidine-4-yl)-dimethyl--amine (compd A 212).
(0.3g 0.97mmol) is dissolved among the DMF (10mL) with (2-chloro-6-methyl-pyrimidine-4-yl)-dimethyl--amine (285mg, 0 97mmol) with 1-(2-fluoro-4-methylsulfonyl-phenyl)-4-(piperidin-4-yl)-1H-pyrazolo [34-d] pyrimidine hydrochloride.Use K at ambient temperature
2CO
3(398mg, 2 91mmol) treatment soln.Pour reactant into H behind the stirring 5h down at 65 ℃
2Among the O (20mL).With ETHYLE ACETATE (30mL) extracting of organic compounds and use brine wash.With ethyl acetate layer through MgSO
4Dry and concentrated in a vacuum.Through SiO
2The purifying resistates produces compd A 212 (312mg, 65 2%).
1H?NMR(400Mz，DMSO-d
6)δ8?69(s，1H)，8?64(s，1H)，8?17(dd，J＝8.4，1?8，1H)，8?08(d，J＝4?2，1H)，8?01(dd，J＝8?4，18，1H)，7?72(s，1H)，5?65(m，1H)，4?23～4.20(m，2H)，3?50～3.46(m，2H)，3?39(s，3H)，3?00(s，6H)，2?13(s，3H)，2?10～2?09(m，2H)，1?77～1?72(m，2H。LCMS?527.5[M+1]。
Instance 9149: preparation 1-(2-fluoro-4-methylsulfonyl-phenyl)-4-[1-(4-methyl-6-tetramethyleneimine-1-base-pyrimidine-2-base)-piperidin-4-yl methyl]-1H-pyrazolo [3,4-d] pyrimidine (compd A 213).
1-(2-fluoro-4-methylsulfonyl-phenyl)-4-(piperidin-4-yl oxygen base)-1H-pyrazolo [3,4-d] pyrimidine hydrochloride (0 3g, 0 97mmol) and (2-chloro-6-methyl-pyrimidine-4-yl)-dimethyl--amine (285mg, 0 97mmol) are dissolved among the DMF (10mL).Use K at ambient temperature
2CO
3(398mg, 2 91mmol) treatment soln.Pour reactant into H behind the stirring 5h down at 65 ℃
2Among the O (20mL).With ETHYLE ACETATE (30mL) extracting of organic compounds and use brine wash.With ethyl acetate layer through MgSO
4Dry and concentrated in a vacuum.Make resistates through SiO
2Purifying produces the crystalline compd A 213 (312mg, 652%) that is white in color.
1H?NMR(400Mz，DMSO-d
6)δ8?68(s，1H)，8?64(s，1H)，8?17(dd，J＝8?4，1?8，1H)，8.08(d，J＝4?2，1H)，8?01(dd，J＝8?4，1?8，1H)，7?62(s，1H)，5?68(m，1H)，4.23～4?19(m，2H)，3.62～3?58(m，4H)，3.50～3?46(m，2H)，3.39(s，3H)，3?00(s，6H)，2?13(s，3H)，2?10～2?09(m，2H)，1?86-1?83(m，4H)，1?77～1?72(m，2H)。LCMS?563?4[M+1]。
Instance 9150: preparation furans-2-base-{ 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone (compd A 14).
Prepare and be beige solid compd A 14 (25mg, 59%) to be similar to instance 9104 described modes.
1HNMR400MHzCDCl
3δ(ppm)2?25(m，2H)，2?48(m，2H)，335(s，3H)；3.95(m，2H)，4?42(m，2H)，5?97(m，1H)，6.75(m，1H)，7.28(d，1H)，7?75(d，1H)，8?35(d，2H)，8?52(s，1H)，8.86(d，2H)，8?93(s，1H)。C
22H
21N
5O
5The accurate mass calculated value 467 13 of S, experimental value 468 4 (MH
+, 100%).
Instance 9.151: preparation { 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-(1-methyl isophthalic acid H-pyrroles-2-yl)-ketone (compd A 15).
Make the compd A 15 (22mg, 54%) that is light gray solid to be similar to instance 925 described modes.
1H?NMR400MHzCDCl
3δ(ppm)8?68(s，1H)，8?63(d，2H)；8.28(s，1H)，8.11(d，2H)，6.73(t，1H)，6?38(m，1H)，6?10(m，1H)，5?71(m，1H)；4?20(m，2H)，3?81(s，3H)，3.65(m，2H)；3?10(s，3H)，2?19(m，2H)，1?96(m，2H)。C
23H
24N
6O
4The accurate mass calculated value 480 16 of S, experimental value 481 3 (MH
+, 100%).
Instance 9.152: preparation 2-{4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-1-pyridin-3-yl-ethyl ketone (compd A 16).
Make the compd A 16 (27mg, 45%) that is yellow solid with the mode that is similar to instance 921.
1H?NMR?400?MHzCDCl
3δ(ppm)9?12(d，1H)，8?73(d，1H)；8?72(s，1H)，8?56(s，1H)；8?50(d，2H)，8?28(m，1H)，8?08(d，2H)，7.50(m，1H)，5?38(m，1H)，3.87(s，2H)，3?21(s，3H)；2?81(m，2H)，2?46(m，2H)，2?04(m，2H)，1?76(m，2H)。C
24H
24N
6O
4The accurate mass calculated value 492 16 of S, experimental value 493.3 (MH
+, 100%).
Instance 9153: preparation 2-{4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-1-thiophene-2-base-ethyl ketone (compd A 22).
Prepare and be beige solid compd A 22 (24mg, 32%) to be similar to instance 921 described modes.
1HNMR400MHzCDCl
3δ(ppm)8?75(s，1H)，8?60(d，1H)，8?49(d，2H)，8?16(m，1H)，8?09(d，2H)，8?02(m，1H)，7.32(m，1H)，5?55(m，1H)；5?05(m，2H)，3?46(m，4H)，3?20(s，3H)，2?25(m，4H)。C
23H
23N
5O
4S
2Accurate mass calculated value 497 12, experimental value 498 3 (MH
+, 100%).
Instance 9.154: preparation 1-{4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-3,3-dimethyl--Ding-2-ketone (compd A 25).
Prepare and be beige solid compd A 25 (29mg, 55%) to be similar to instance 921 described modes.
1HNMR400MHzCDCl
3δ(ppm)8.69(s，1H)，8?49(d，1H)；8?40(d，2H)；8?01(m，2H)，5?48(m，1H)，4?49(m，2H)，3?40(m，1H)，3?12(s，3H)，2.98(m，3H)，2?12(m，4H)，1?03(s，9H)。C
23H
29N
5O
4The accurate mass calculated value 471 19 of S, experimental value 472 4 (MH
+, 100%).
Instance 9155: preparation { 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-(5-methyl-pyridin-3-yl)-ketone (compd A 18).
Make and be solid compd A 18 (39mg, 66%) to be similar to instance 925 described modes.
1H?NMR?400MHzCDCl
3(ppm)8?82(s，1H)，8?67(s，1H)，8?58(m，2H)，8?51(m，1H)，8.46(m，1H)；8?17(m，2H)；7.71(m，1H)；5?71(m，1H)，4?06(m，1H)，3?62(m，2H)，3?29(s，3H)，2?36(s，3H)，2?17(m，2H)，1?89(m，2H)。C
24H
24N
6O
4The accurate mass calculated value 492 16 of S, experimental value 493.3 (MH
+, 100%).
Instance 9156: preparation { 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-(2-methyl-pyridin-3-yl)-ketone (compd A 19).
Obtain to be beige solid compd A 19 (35mg, 48%) to be similar to instance 925 described modes.
1H?NMR400MHzCDCl
3δ(ppm)8?74(s，1H)，8.58(s，1H)；8?55(m，1H)，8.49(m，2H)，8?08(m，2H)；7?87(m，1H)；7?44(m，1H)，5?63(m，1H)，3?59(m，2H)；3?38(m，1H)，3?24(m，1H)，3?21(s，3H)，2.45(s，3H)，2.16(m，1H)；1.98(m，1H)，1?84(m，1H)，1?72(m，1H)。C
24H
24N
6O
4The accurate mass calculated value 492 16 of S, experimental value 493 3 (MH
+, 100%).
Instance 9.157: preparation { 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-(6-methyl-pyridin-3-yl)-ketone (compd A 20).
Obtain to be beige solid compd A 20 (40mg, 55%) to be similar to instance 925 described modes.
1H?NMR?400MHzCDCl
3δ(ppm)8?59(s，1H)，8?43(s，1H)，8?42(m，1H)；8?34(m，2H)，7?94(m，2H)，7?75(m，1H)，7.29(m，1H)，5.49(m，1H)，3?31(m，4H)；3.06(s，3H)，2?35(s，3H)，1?93(m，2H)，1?65(m，2H)。C
24H
24N
6O
4The accurate mass calculated value 492 16 of S, experimental value 493.3 (MH
+, 100%).
Instance 9.158: preparation 4-[1-{4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-5-methyl-isoxazole-3-bases)-ketone (compd A 21)
To be similar to the compd A 21 (18mg, 24%) that instance 925 described modes obtain to be little brown solid.
1HNMR400MHzCDCl
3?δ(ppm).8?46(s，1H)，8?40(d，2H)，8?06(s，1H)，7?89(d，2H)，6?11(s，1H)，5.52(m，1H)，3?98(m，2H)，3?55(m，2H)，2.89(s，3H)，2?28(s，3H)；1?97(m，2H)，1?82(m，2H)。C
22H
22N
6O
5The accurate mass calculated value 482 14 of S, experimental value 483 2 (MH
+, 100%).
Instance 9159: preparation { 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base is amino]-piperidines-1-yl }-(6-methyl-pyridin-3-yl)-ketone (compound A-28 0).
To be similar to the compound A-28 0 (75mg, 58%) that instance 994 described modes obtain to be light yellow solid.C
22H
27FN
6O
4The accurate mass calculated value 490.18 of S, experimental value 491 3 (MH
+, 100%).
Instance 9160: preparation 4-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-t-butyl formate (compd A 74).
To be similar to the instance 9.1 described modes solid compd A 74 (30mg, 23%) that obtains to be white in color.
1HNMR400MHzCDCl
3δ(ppm)8?56(s，1H)，8?26(s，1H)；7?88(m，3H)，5?54(m，1H)，3?81(m，2H)，3?27(m，2H)，3?06(s，3H)，2.03(m，2H)，1?80(m，2H)，1.43(s，9H)。C
22H
26FN
5O
5The accurate mass calculated value 491 16 of S, experimental value 492 4 (MH
+, 100%).
Instance 9.161: preparation 4-[6-dimethylamino-1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-t-butyl formate (compound A-28 9).
Step 1: preparation 1-chloro-N '-[4-cyanic acid-2-(4-methylsulfonyl-phenyl)-2H-pyrazole-3-yl]-N, N-dimethyl--carbonamidine.
With anhydrous 1, (12g is 457mmol) with carbonyl chloride imido (0 900g, 708mmol) backflow 4h for the 5-amino-1-in the 2-methylene dichloride (4-methylsulfonyl-phenyl)-1H-pyrazoles-4-nitrile.Decompression removes solvent and produces 1-chloro-N '-[4-cyanogen-2-(4-methylsulfonyl-phenyl)-2H-the pyrazole-3-yl]-N that is light yellow solid, N-dimethyl--carbonamidine (1.3g, 80%) through flash chromatography (30 to 50% ethyl acetate/hexane) purifying resistates.C
14H
14ClN
5O
2The accurate mass calculated value 351 06 of S, experimental value 352.20 (MH
+, 100%).
Step 2: preparation [4-chloro-1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-6-yl]-d) methyl-amine.
Make the dry hydrogen chloride air communication cross 1, the 1-chloro-N ' in the 2-methylene dichloride (20mL)-[4-cyanic acid-2-(4-methylsulfonyl-phenyl)-2H-pyrazole-3-yl]-N, N-dimethyl--carbonamidine (0 600g, 1 70mmol) solution lasts 1h.At room temperature with solution stirring 3 days.Decompression removes solvent also with the washed with dichloromethane crude product for several times.Make [4-chloro-1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-6-yl]-dimethyl--amine recrystallize in methylene dichloride also it reclaimed (0 4g, 67%) as the beige solid through filtering.C
14H
14ClN
5O
2The accurate mass calculated value 351 06 of S, experimental value 352 20 (MH
+, 100%).
Step 3: preparation 4-[6-dimethylamino-1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-t-butyl formate (compound A-28 9).
To be similar to the instance 9.1 described modes solid compound A-28 9 (100mg, 90%) that obtains to be white in color.
1HNMR(400MHz?DMSO-d
6)δ(ppm)8?37(d，2H)，8?02(s，1H)，7?88(d，2H)，5.26(m，1H)，3?49(m，2H)；3?12(m，5H)，3?05(s，6H)，1?79(m，2H)；1?50(m，2H)，1?22(s，9H)。C
24H
32N
6O
5The accurate mass calculated value 516 22 of S, experimental value 517 3 (MH
+, 100%).
Instance 9162: preparation 4-({ ethyl-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-yl]-amino }-methyl)-piperidines-1-isopropyl formate (compound A-28 7).
To be similar to instance 924 described modes through using compound A-28 8 preparation compound A-28s 7.The acquisition solid product (32mg, 50%) that is white in color.
1HNMR400MHzCDCl
3δ(ppm)8.41(s，1H)，8?13(s，1H)，7.86(m，2H)，7.79(m，1H)；4?85(m，1H)，4?41(s，2H)，3?66(m，4H)，3?05(s，3H)，2.67(m，2H)，2?08(d，1H)，1?65(s，2H)；1.39(m，4H)，1?18(d，6H)。C
24H
31FN
6O
4The accurate mass calculated value 518.21 of S, experimental value 519 5 (MH
+, 100%).
Instance 9163: preparation 4-[1-(2-dimethylamino-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-t-butyl formate (compd A 100).
Step 1: preparation 1-(2-dimethylamino-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-alcohol.
With 1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-alcohol (0 520g, 1 68mmol) be dissolved in DMSO (3mL) and add n n dimetylaniline (2MTHF solution) (4mL, 150mmol).Under 120 ℃ with mixture heating up 15h.Decompression removes solvent and is beige solid 1-(2-dimethylamino-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-alcohol (0.500g, 89%) through the generation of HPLC purifying crude product.C
14H
15N
5O
3The accurate mass calculated value 333 09 of S, experimental value 334 4 (MH
+, 100%).
Step 2: preparation 4-[1-(2-dimethylamino-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-t-butyl formate (compd A 100).
With 1-(2-dimethylamino-4-methylsulfonyl-phenyl)-1H-pyrazolo [3; 4-d] pyrimidine-4-alcohol (66mg; 0 200mmol); 4-hydroxy-piperdine-1-t-butyl formate (61mg, 0.300mmol) and triphenylphosphine (52mg, 0 200mmol) be dissolved in toluene (5mL) and under 0 ℃, mixture stirred 15min.Then add azoformic acid diisopropyl fat (28 μ L, 0.200mmol) and make reaction at room temperature carry out 16h.Decompression removes solvent and passes through HPLC purifying crude product.Acquisition is the compd A 100 of light yellow solid.C
24H
32N
6O
5The accurate mass calculated value 516 22 of S, experimental value 517 3 (MH
+, 100%).
1HNMR(400MHz?CDCl
3)δ(ppm)8?50(s，1H)，8?22(s，1H)，7?42(m，3H)，5?52(m，1H)，3?81(m，2H)；3.26(m，?2H)，3.03(s，3H)，2?47(s，6H)，2?03(m，2H)，1?80(m，2H)，1?42(s，9H)。
Instance 9164: preparation 4-{2-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-ethyl }-piperazine-1-ethyl formate (compd A 103).
To be similar to the instance 9.131 described modes solid compd A 103 (46mg, 49%) that obtains to be white in color.
1HNMR(400MHz?DMSO-d
6)δ(ppm)8?78(s，1H)，8?66(s，1H)，8?50(m，2H)，8?10(m，2H)，4?90(s，2H)，4?00(m，4H)，3.49(m，5H)，3?12(s，3H)，3.02(m，3H)，1.14(t，3H)。C
21H
26N
6O
5The accurate mass calculated value 474.17 of S, experimental value 475.3 (MH
+).
Instance 9165: preparation 4-{2-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-propyl group }-piperazine-1-ethyl formate (compd A 104).
To be similar to the instance 9.131 described modes solid compd A 104 (47mg, 48%) that obtains to be white in color.
1HNMR(400MHz?DMSO-d
6)δ(ppm)8?66(s，1H)，8?45(s，1H)，8?37(m，2H)，7?98(m，2H)，5?73(m，1H)；3?87(m，4H)；337(m，5H)，3?06(s，3H)；3.02(m，3H)；1?30(d，3H)，1?14(t，3H)。C
22H
28N
6O
5The accurate mass calculated value 488.18 of S, experimental value 489 30 (MH
+, 100%).
Instance 9166: preparation (5-fluoro-pyridine-2-yl)-{ 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone (compd A 171).
To be similar to the compd A 171 (155mg, 507%) that instance 925 described modes obtain to be orange solids.C
23H
21FN
6O
4The accurate mass calculated value 496 13 of S, experimental value 497 10 (MH
+, 100%).
Instance 9167: preparation (2-chloro-5-fluoro-pyridin-3-yl)-{ 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone (compd A 173).
To be similar to the compd A 173 (14 9mg, 46 2%) that instance 925 described modes obtain to be little brown solid.C
23H
20ClFN
6O
4The accurate mass calculated value 530 09 of S, experimental value 531 10 (MH
+, 100%).
Instance 9168: preparation { 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-(4-methoxyl group-pyridine-2-yl)-ketone (compd A 177).
Obtain to be beige solid compd A 177 (11 7mg, 37 6%) to be similar to instance 925 described modes.C
24H
24N
6O
5The accurate mass calculated value 508 15 of S, experimental value 509 1 (MH
+, 100%).
Instance 9.169: preparation (2-fluoro-pyridin-3-yl)-{ 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone (compd A 179).
To be similar to the compd A 179 (11 7mg, 37 6%) that instance 925 described modes obtain to be orange solids.C
23H
21FN
6O
4The accurate mass calculated value 496 13 of S, experimental value 497 10 (MH
+, 100%).
Instance 9.170: preparation (6-fluoro-pyridin-3-yl)-{ 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone (compd A 180).
To be similar to the compd A 180 (15 5mg, 50%) that instance 925 described modes obtain to be little brown solid.C
23H
21FN
6O
4The accurate mass calculated value 496 13 of S, experimental value 49710 (MH
+, 100%).
Instance 9171 preparations (4-iodo-pyridine-2-yl)-{ 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-methanone compounds A167).
To be similar to the compd A 167 (15 5mg, 50%) that instance 925 described modes obtain to be little brown solid.C
23H
21IN
6O
4The accurate mass calculated value 604 04 of S, experimental value 605 1 (MH
+, 100%).
Instance 9.172: preparation 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base }-piperidines-1-yl }-(4-methoxyl group-thiene-3-yl-)-ketone (compd A 181).
To be similar to the instance 9.25 described modes solid compd A 181 (7 2mg, 23%) that obtains to be white in color.C
23H
23N
5O
5S
2Accurate mass calculated value 513 11, experimental value 514.2 (MH
+, 100%).
Instance 9.173: preparation 4-(1-benzyl-azetidine-3-base oxygen base)-1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine (compd A 23).
(0 59mmol 117mg) is dissolved in the N,N-DIMETHYLACETAMIDE (2mL) also at room temperature with its stirring 30min with sodium hydride with 1-benzyl-azetidine-3-alcohol hydrochloride.Add slowly that 4-chloro-1-(4-methylsulfonyl-phenyl)-(0 49mmol 150mg) and under 70 ℃ stirs 20min with mixture to 1H-pyrazolo [3,4-d] pyrimidine.The reaction mixture water is ended then to use ethyl acetate extraction.Remove organic solvent in the vacuum and produce the solid compd A 23 (88mg, 41%) that is white in color through the flash chromatography purifying.
1HNMR(400MHz，DMSO-d
6)δ(ppm)8?90(s，1H)，8?53(s，1H)，8.30(d，2H)，8.16(d，2H)，7?43(m，5H)，6?19(m，1H)，4?59(m，2H)；4.42(d，1H)，4?00(d，1H)，3?65(d，1H)，3?35(m，1)，3?30(s，3H)。
Instance 9.174: preparation 3-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-azetidine-1-isopropyl formate (compd A 47).
Step 1: preparation 4-(azetidine-3-base oxygen base)-1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine.
(1-benzyl-azetidine-3-base oxygen base)-(0 01mmol 46mg) is dissolved in the mixture of ETHYLE ACETATE (5mL) and methyl alcohol (5mL) 1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine with 4-.Palladium catalyst (30mg, 65 weight %) is added reaction.At room temperature with under the normal atmosphere mixture is exposed to lasting 60min in the hydrogen.Make mixture through zeyssatite to remove palladium catalyst.Remove organic solvent in a vacuum and its purifying is produced the solid 4-that is white in color (azetidine-3-base oxygen base)-1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine (11mg, 5%) through flash chromatography.
1H?NMR(400MHz，MeOH-d
4)δ(ppm)8?45(m，2H)；8.37(d，2H)，8?05(d，2H)，4?54(m，1H)；4?35(dd，2H)，3?69(m，2H)，3?09(s?3H)。LCMS(ESI)，m/z?346.2(M+H+，100％)。
Step 2: preparation 3-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-azetidine-1-isopropyl formate (compd A 47).
To be similar to the instance 924 described modes solid compd A 47 (26mg, 55%) that obtains to be white in color.
1H?NMR(400MHz，CDCl
3)δ(ppm)8?66(s，1H)，8.62(d，2H)；8.31(s，1H)；8.11(d，2H)；5.65(m，1H)，4?93(h，1H)，4?48(m，2H)，4?18(m，2H)，3.11(s，3H)，1?25(d，6H)。LCMS(ESI)，m/z?432?3(M+H+，100％)。
Instance 9175: preparation { 4-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-(3-trifluoromethoxy-phenyl)-ketone (compd A 197).
To be similar to the instance 928 described modes solid compd A 197 (221mg, 46%) that obtains to be white in color.C
25H
22F
3N
5O
2The accurate mass calculated value 579.56 of S, experimental value 580.4 (MH
+).
Instance 9176: preparation 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-propyl formate (compd A 49).
To be similar to the instance 924 described modes solid compd A 49 (36mg, 46%) that obtains to be white in color.
1HNMR(400MHz，CDCl
3)δ(ppm)8?69(s，1H)，8.62(d，2H)；8?26(s，1H)，8.10(d，2H)；5?61(h，1H)；4?22(t，2H)，4?08(m，2H)，3.40(m，2H)；3.10(s，3H)，2?11(m，2H)，1?87(m，2H)，1?64(s，2H)，0?97(t，3)。LCMS(ESI)，m/z?460?3(MH+，100％)。
Instance 9 177: preparation 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-cyclohexyl formate (compd A 63).
With carbonyl dimidazoles (028mmol, 46mg) and hexalin (0 28mmol, 34 μ L) be dissolved among the DMF (2mL) and and at room temperature stir 30min it.Then, (0 16mmol 60mg) continues stirring 24h down with triethylamine (0.84mmol, 118 μ L) and at 60 ℃ to add 1-(4-methylsulfonyl-phenyl)-4-(piperidin-4-yl oxygen base)-1H-pyrazolo [3,4-d] pyrimidine hydrochloride.The reaction mixture water is ended then to use ethyl acetate extraction.Remove organic solvent in the vacuum and produce the solid compd A 63 that is white in color through the HPLC purifying.
1HNMR(400MHz，CDCl
3)δ(ppm)：8.67(s，1H)；8.61(d，2H)，8?26(s，1H)，8?11(d，2H)，5?62(h，1H)，4?71(h，1H)，3?91(m，2H)，3?38(m，2H)，3?10(s，3H)，2?10(m，2H)；1?87(m，4H)，1?65(m，6H)，1?28(m，2H)。LCMS(ESI)，m/z?500?4(MH+，100％)。
Instance 9178: preparation 4-[1-{4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-formic acid tetrahydrochysene-pyrans-4-base ester (compd A 64).
To be similar to the instance 9177 described modes solid compd A 64 (7mg, 9%) that obtains to be white in color.
1HNMR(400MHz，CDCl
3)δ(ppm)8?67(s，1H)，8?62(d，2H)，8?26(s，1H)，8?11(d，2H)，5?13(h，1H)，4?89(h，1H)，3?92(m，4H)，3?58(m，2H)，3?40(m，2H)，3?11(s，3H)，2?12(m，2H)，1?90(m、4H)，1?71(m，2H)。LCMS(ESI)，m/z?502?3(MH+，100％)。
Instance 9179: preparation 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-formic acid ring pentyl ester (compd A 65).
To be similar to the instance 9177 described modes solid compd A 65 (13mg, 18%) that obtains to be white in color.
1HNMR(400MHz，CDCl
3)δ(ppm)8?67(s，1H)，8?62(d，2H)；8.26(s，1H)，8?11(d，2H)，5?61(h，1H)，5?14(m，1H)，3?89(m，2H)，3?36(m，2H)，3?10(s，3H)，2?10(m，2H)；1.88(m，4H)，1.74(m，4H)，1?61(m，2H)。LCMS(ESI)，m/z486?3(MH+，100％)。
Instance 9 180: preparation 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-formic acid tetrahydrochysene-furans-3-base ester (compd A 67).
To be similar to the instance 9177 described modes solid compd A 67 (12mg, 16%) that obtains to be white in color.
1HNMR(400MHz，CDCl
3)δ(ppm)：8?67(s，1H)，8?61(d，2H)，8?26(s，1H)，8?10(d，2H)，5.63(h，1H)，5?30(m，1H)，3?91(m，6H)，3?41(m，2H)，3?11(s，3H)，2?18(m，4H)，1?95(m，2H)。LCMS(ESI)，m/z?488?3(MH+，100％)。
Instance 9 181: preparation 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-formic acid tetrahydrochysene-furans-3-base ester (compd A 66).
To be similar to the instance 9177 described modes solid compd A 65 (11mg, 15%) that obtains to be white in color.
1HNMR(400MHz，CDCl
3)δ(ppm)8?67(s，1H)，8?61(d，2H)；8.26(s，1H)，8?11(d，2H)，5?63(h，1H)；5?29(m，1H)，3?90(m，6H)，3.41(m，2H)，3?11(s，3H)，2?18(m，4H)，1?97(m，2H)。LCMS(ESI)，m/z?488?2(MH+，100％)。
Instance 9182: preparation 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-formic acid tetrahydrochysene-thiapyran-4-base ester (compd A 68).
To be similar to the instance 9177 described modes solid compd A 68 (4mg, 5%) that obtains to be white in color.
1HNMR(400MHz，CDCl
3)δ(ppm)8?67(s，1H)，8?61(d，2H)；8.26(s，1H)，8?11(d，2H)，5?63(h，1H)；4.80(h，1H)，4.22(m，2H)；3?41(m，2H)，3.11(s，3H)；2.79(m，2H)，2?64(m，2H)，2?15(m，4H)；1.91(m，4H)。LCMS(ESI)，m/z?518?2(MH+，100％)。
Instance 9183: preparation 4-[1-{4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-formic acid ring butyl ester (compd A 69).
To be similar to the instance 9177 described modes solid compd A 65 (13mg, 19%) that obtains to be white in color.
1H-NMR(400MHz，CDCl
3)δ(ppm)8?67(s，1H)，8?6(d，2H)，8?26(s，1H)，8.10(d，2H)；5.632(h，1H)，4?97(p，1H)；3?89(m，2H)，3?40(m，2H)，3?10(s，3H)，2?36(m，2H)，2?10(m，4H)，1.88(m，4H)。LCMS(ESI)，m/z?472.4(MH+，100％)。
Instance 9.184: preparation 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [34-d] pyrimidine-4-base oxygen base]-piperidines-1-pyridine carboxylic acid-3-ylmethyl ester (compound A-28 1).
To be similar to the instance 9177 described modes solid compound A-28 1 (31mg, 28%) that obtains to be white in color.
1HNMR(400MHz，CDCl
3)δ(ppm)8?93(s，1H)，8?81(d，1H)；8.67(s，1H)，8?61(d，2H)，8?30(d，1H)，?8?26(s，1H)；8.11(d，2H)，7?84(m，1H)，5.65(h，1H)，5.33(s，2H)；3?91(m，2H)；3?50(m，2H)，3?11(s，3H)，2?15(m，2H)，1?91(m，2H)。LCMS(ESI)，m/z?509?0(MH+，100％)。
Instance 9.185: preparation 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-formic acid 2-pyridin-3-yl-ethyl ester (compound A-28 2).
To be similar to the instance 9177 described modes solid compound A-28 2 (35mg, 30%) that obtains to be white in color.
1H NMR (400MHz, MeOH-d
4) δ (ppm) 7 54 (single broad peak, 1H), 7 44 (m, 1H), 7 36 (m, 3H), 7 24 (d, 1H), 7 09 (s, 1H), 6 85 (d, 2H), 6 71 (m, 1H), 4 37 (h, 1H), 34 (t, 2H); 2.52 (m, 2H); 2.10 (m, 2H); 1 97 (t, 2H), 1 94 (s, 3), 0.81 (m, 2H), 0 56 (m, 2H).LCMS(ESI)，m/z?523?2(MH+，100％)。
Instance 9 186: preparation 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-formic acid 3-pyridin-3-yl-propyl ester (compound A-28 3)
To be similar to the instance 9177 described modes solid compound A-28 3 (28mg, 24%) that obtains to be white in color.
1HNMR (400MHz, MeOH-d
4) δ (ppm) 7 64 (single broad peak, 1H), 7 38 (m, 4H), 7 16 (d, 1H), 7.10 (s, 1H), 6 84 (d, 2H), 6 66 (m, 1H), 4 38 (h, 1H); 2.89 (t, 2H), 2 57 (m, 2H), 2 12 (m, 2H), 1 89 (s, 3H), 1 68 (t, 2H), 0 81 (m, 4H), 0 59 (m, 2H).LCMS(ESI)，m/z?537?2(MH+，100％)。
Instance 9 187: preparation 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-formic acid 2-dimethylamino-ethyl ester (compound A-28 4).
To be similar to the instance 9177 described modes solid compound A-28 4 (16mg, 15%) that obtains to be white in color.
1HNMR(400MHz，CDCl
3)δ(ppm)7?37(m，3H)，7?11(s，1H)，6?83(d，2H)，4?39(h，1H)，2?95(t，2H)，2?61(m，2H)，2?03(m，2H)，1?89(s，3H)，1?37(t，2H)，1?03(s，6H)；0.86(m，2H)，0?60(m，2H)。LCMS(ESI)，m/z?489?2(MH+，100％)。
Instance 9188: preparation 4-{ [1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-yl]-methyl-amino }-piperidines-1-t-butyl formate (compound A-28 5)
To be similar to the compound A-28 5 (750mg, 95%) that instance 9130 described modes obtain to be yellow solid.
1HNMR (400MHz, CDCl
3) δ (ppm) S 59 (d, 2H), 8 51 (single broad peak, 1H), 8 12 (s, 1H); 8.08 (d, 2H), 4 18 (m, 2H), 3 59 (single broad peak, 2H); 3.10 (s, 3H), 2 73 (m, 2H), 1 91 (m, 1H), 1.79 (m, 2); 1 70 (single broad peak, 3H), 1.43 (s, 9H).LCMS(ESI)，m/z?487?1(MH+，100％)。
Instance 9189: preparation 1-(4-{ [1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-yl]-methyl-amino }-piperidines-1-yl)-3,3-dimethyl--Ding-2-ketone (compd A 90).
To be similar to the instance 921 described modes solid compd A 90 (14mg, 12%) that obtains to be white in color.
1H NMR (400MHz, CDCl
3) δ (ppm) 8 58 (d, 2H), 8.09 (t, 3H), 3.59 (single broad peak, 2H), 3 39 (s, 2H), 3 09 (s, 3H), 2 95 (m, 2H), 2 05 (m, 2H), 1 79 (m, 3H), 1 66 (m, 4H), 1 16 (s, 9H).LCMS(ESI)，m/z485?3?(MH+，100％)。
Instance 9.190: preparation 4-{ [1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-yl]-methyl-amino }-piperidines-1-formic acid ring butyl ester (compd A 91)
To be similar to the instance 9.177 described modes solid compd A 91 (62mg, 35%) that obtains to be white in color.
1HNMR (400MHz, CDCl
3) δ (ppm) 8 60 (d, 2H), 8 57 (single broad peak, 1H), 8 13 (s, 1H), 8 07 (d, 2H), 4 93 (p, 1H), 4 22 (m, 2H), 3.58 (single broad peak, 2H), 3.10 (s, 3H), 2 75 (single broad peak, 2H), 2 34 (m, 2H); 2 06 (m, 2H), 1 93 (m, 1H), 1.75 (m, 7H).LCMS(ESI)，m/z?485?2(MH+，100％)。
Instance 9 191: preparation 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base sulfenyl]-piperidines-1-t-butyl formate (compd A 102).
With 4-chloro-1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine (123mmol; 250mg), 4-sulfydryl-piperidines-1-t-butyl formate (123mmol; 268mg) and salt of wormwood (14mmol 203mg) is dissolved among the DMF (10mL) and at room temperature it is stirred 60mm.Monitor said process by thin layer chromatography and LCMS.The reaction mixture water is ended then to use ethyl acetate extraction.Remove organic solvent in the vacuum and produce the solid compd A 102 (264mg, 66%) that is white in color through the tubing string purification by chromatography.
1HNMR(400MHz，CDCl
3)δ(ppm)8.83(s，1H)，8?61(d，2H)，8.24(s，1H)，8?11(d，2H)，4.42(h，1H)；4?00(m，2H)；350(m，2H)，3?15(s，3H)，2?19(m，2H)；1?77(m，2H)，1?46(s，9H)。LCMS(ESI)，m/z?490?3(MH+，100％)。
Instance 9192: preparation 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-sulfinyl]-piperidines-1-t-butyl formate (compd A 105).
(0 51mmol 250mg) is dissolved in 1, in the 2-ethylene dichloride (15mL) with compd A 102.To wherein add MCPBA (0 51mmol, 88mg).At room temperature with the mixture stirred overnight.Monitor said process by thin layer chromatography and LCMS.With the aqueous solution (the pH value is 10) of ammonium chloride and the solution washing reaction mixture of sodium hydrogencarbonate.Use the dichloromethane extraction product.Remove organic solvent in the vacuum and produce the solid compd A 105 (29mg, 12%) that is white in color through the HPLC purifying.
1HNMR(400MHz，CDCl
3)δ(ppm)9.12(s，1H)，9?03(s，1H)，8?66(d，2H)，8.15(d，2H)；4?22(m，1H)，4?20(m，2H)，3?43(m，1H)，3?13(s，3H)；2?74(m，2H)，2.26(m，1H)，2?00(m，2H)，1?57(s，9H)。LCMS(ESI)，m/z?506?2(MH+，100％)。
Instance 9193: preparation 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-alkylsulfonyl]-piperidines-1-t-butyl formate (compd A 106).
(0.31mmol 150mg) is dissolved in 1, in the 2-ethylene dichloride (15mL) with compd A 102.To wherein add excessive MCPBA (1 5mmol, 268mg).Make mixture backflow 10h.Monitor said process by thin layer chromatography and LCMS.With the aqueous solution (the pH value is 10) of ammonium chloride and the solution washing reaction mixture of sodium hydrogencarbonate.Use the dichloromethane extraction product.Remove organic solvent in the vacuum and produce the solid compd A 106 (46mg, 25%) that is white in color through the HPLC purifying.
1HNMR(400MHz，CDCl
3)δ(ppm)：9.31(s，1H)；8?86(s，1H)；8?65(d，2H)；8.17(d，2H)，4?25(m，3H)；3.90(m，1H)，3?13(s，3H)，2?80(m，1H)，2?03(m，2H)，1?86(m，2H)，1.70(s，9H)。LCMS(ESI)，m/z?5223(MH+，100％)。
Instance 9194: preparation 4-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base sulfenyl]-piperidines-1-butyl formate (compd A 108).
Step 1: preparation 1-(2-fluoro-4-methylsulfonyl-phenyl)-4-(piperidin-4-yl sulfenyl)-1H-pyrazolo [3,4-d] pyrimidine.
(122mmol 620mg) is dissolved in the ethylene dichloride (15mL) with compd A 107.The 4MHCl solution in wherein adding diox (8mL) at room temperature.Under 40 ℃, reactant was stirred 30 minutes.Through LCMS monitoring reaction process.In a vacuum organic solvent evaporation is produced solid 1-(2-fluoro-4-methylsulfonyl-phenyl)-4-(piperidin-4-yl sulfenyl)-1H-pyrazolo [3, the 4-d] pyrimidine that is white in color.(530mg，98％)。LCMS(ESI)，m/z?408.2(MH+，100％)。
Step 2: preparation 4-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base sulfenyl]-piperidines-1-butyl formate (compd A 108).
To be similar to the instance 9177 described modes solid compd A 108 (43mg, 54%) that obtains to be white in color.
1HNMR(400MHz，CDCl
3)δ(ppm)8?72(s，1H)，8?23(s，1H)，7?87(m，3H)，4?36(h，1H)，4?01(m，4H)，3?16(m，2H)，3?05(s，3H)，2?12(m，2H)，1?70(m，2H)，1?58(m，2H)，1?35(s，2H)；0?88(t，3H)。LCMS(ESI)，m/z?508?4(MH+，100％)。
Instance 9195: preparation 4-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base sulfenyl]-piperidines-1-formic acid 2-methoxyl group-ethyl ester (compd A 109).
To be similar to the instance 9177 described modes solid compd A 109 (4mg, 5%) that obtains to be white in color.
1H?NMR(400MHz，CDCl
3)δ(ppm)：8.71(s，1H)，8?24(s，1H)，7?87(m，3H)，4?37(m，1H)，4?20(m，2H)，3?99(m，2H)，3?56(m，2H)，3?33(s，3H)，3?17(m，2H)，3?06(s，3H)；2?12(m，2H)；1.72(m，2H)。LCMS(ESI)，m/z?510?3(MH+，100％)。
Instance 9196: preparation 4-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base sulfenyl]-piperidines-1-formic acid 3,3-dimethyl--butyl ester (compd A 110).
Prepare the solid compd A 110 that is white in color (22mg, 24%) to be similar to instance 9.177 described modes.
1HNMR (400MHz, CDCl
3) δ (ppm): 8.71 (s, 1H); 8.23 (s, 1H), 7 87 (m, 3H), 4 36 (h, 1H), 4 10 (t, 2H), 396 (single broad peak, 2H), 3 15 (m, 2H), 3 04 (s, 3H), 2 12 (m, 2H), 1 71 (m, 2H), 1 51 (t, 2H), 0.85 (s, 9H).LCMS(ESI)，m/z?536?2(MH+，100％)。
Instance 9197: preparation 4-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base sulfenyl]-piperidines-1-formic acid 4-methyl-pentyl ester (compd A 111).
To be similar to the instance 9177 described modes solid compd A 111 that obtains to be white in color.LCMS(ESI)，m/z?536.2?(MH+，100％)。
Instance 9198: preparation { 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-(5-morpholine-4-ylmethyl-furans-2-yl)-ketone (compd A 116).
With 5-morpholine-4-ylmethyl-furans-2-formic acid (0 12mmol, 25mg) and isopropyl chlorocarbonate (0 12mmol, 17 μ L) and triethylamine (0 12mmol, 17 μ L) be dissolved among the DMSO (2mL) and at room temperature it stirred 30min.Then add 1-(4-methylsulfonyl-phenyl)-4-(piperidin-4-yl oxygen base)-1H-pyrazolo [3,4-d] pyrimidine (0.12mmol, 50mg) and excess of triethylamine.Under 120 ℃, mixture is heated 5min in microwave.Monitor said reaction process by thin layer chromatography and LCMS.Produce the solid compd A 116 that is white in color through the HPLC purifying.LCMS(ESI)，m/z?5673(MH+，100％)。
Instance 9199: preparation 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-formic acid 2-tetramethyleneimine-1-base-ethyl ester (compd A 121).
To be similar to the instance 9.177 described modes solid compd A 121 (29mg, 27%) that obtains to be white in color.LCMS(ESI)，m/z?5153(MH+，100％)。
Instance 9200: preparation 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-formic acid 2-morpholine-4-base-ethyl ester (compd A 122).
To be similar to the instance 9177 described modes solid compd A 122 (20mg, 20%) that obtains to be white in color.LCMS(ESI)，m/z?531.3(MH+，100％)。
Instance 9201 preparation 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-ethyl formate (compd A 123).
With 1-(4-methylsulfonyl-phenyl)-4-(piperidin-4-yl oxygen base)-1H-pyrazolo [3; 4-d] and the pyrimidine hydrochloride (0 17mmol, 70mg), Vinyl chloroformate (0 25mmol; 25 μ L) and triethylamine (0 51mmol, 72 μ L) be dissolved among the DMF (2mL) and and at room temperature stir 60min it.Monitor the process of said reaction by TLC and LCMS.Water stopped reaction mixture.Use the ethyl acetate extraction product.Remove organic solvent in the vacuum and produce the solid compd A 123 (14mg, 15%) that is white in color through the HPLC purifying.C
20H
23N
5O
5The accurate mass calculated value 445 49 of S, experimental value 446 10 (MH
+).
Instance 9202: preparation ethyl-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-yl]-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] dipyridyl-4-ylmethyl)-amine (compd A 126).
Under 165 ℃ under microwave radiation with the ethyl among the DMF (10mL)-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3; 4-d] pyrimidine-4-yl]-piperidin-4-yl methyl-amine hydrochlorate (30mg; 0 064mmol), 2-bromopyridine (0 62 μ L; 0 64mmol) and triethylamine (26 μ L, 0.19mmol) mixture heating up 30min.Produce the solid compd A 126 (5mg, 15%) that is white in color through HPLC purifying crude mixture.C
25H
28FN
7O
2The accurate mass calculated value 509 2 of S, experimental value 510 5 (MH
+).
Instance 9203: preparation ethyl-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-yl]-(5 '-trifluoromethyl-3,4,5,6-tetrahydrochysene-2H-[1,2 '] dipyridyl-4-ylmethyl)-amine (compd A 127).
Under 165 ℃ under microwave radiation with the ethyl among the DMF (10mL)-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3; 4-d] pyrimidine-4-yl]-piperidin-4-yl methyl-amine hydrochlorate (30mg; 0 064mmol), 2-bromo-5-5-flumethiazine (188mg; 0 83mmol) and triethylamine (27 μ L, 0 19mmol) mixture heating up 20min.Produce the solid compd A 127 (19mg, 51%) that is white in color through HPLC purifying crude mixture.C
26H
27F
4N
7O
2The accurate mass calculated value 557.19 of S, experimental value 578 3 (MH
+).
Instance 9204: preparation [1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-yl]-(5 '-trifluoromethyl-3,4,5,6-tetrahydrochysene-2H-[1,2 '] dipyridyl-4-yl)-amine (compd A 128).
Under 165 ℃ under microwave radiation with the [1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3 among the DMF (10mL); 4-d] pyrimidine-4-yl]-piperidin-4-yl-amine (100mg; 0 24mmol), 2-bromo-4-5-flumethiazine (166mg; 0 73mmol) and salt of wormwood (102mg, 0.73mmol) mixture heating up 20min.Produce the solid compd A 128 (41mg, 32%) that is white in color through HPLC purifying crude mixture.C
23H
22F
3N
7O
2The accurate mass calculated value 517.15 of S, experimental value 518.2 (MH
+).
Instance 9205: preparation [1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-yl]-[1-(the 3-sec.-propyl-[1,2,4] oxadiazole-5-ylmethyls)-tetramethyleneimine-3-yl]-amine (compd A 133).
Make 1-(the 3-sec.-propyl-[1 among the THF (20mL); 2; 4] oxadiazole-5-ylmethyl)-tetramethyleneimine-3-base amine (354mg, 1 68mmol), 4-chloro-1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine (500mg; 1 53mmol) and salt of wormwood (3 18g, 23mmol) mixture backflow 2h.In reaction mixture, add entry and use the ethyl acetate extraction product.Through MgSO
4Dry ethyl acetate layer.The dried in vacuum organic layer produces the solid compd A 133 (700mg, 91%) that is white in color.C
22H
25FN
8O
3The accurate mass calculated value 500 18 of S, experimental value 501 1 (MH
+).
Instance 9206: preparation [1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-yl]-[1-(the 3-sec.-propyl-[1,2,4] oxadiazole-5-ylmethyls)-tetramethyleneimine-3-yl]-amine (compd A 134).
To be similar to the instance 9.205 described modes solid compd A 134 (712mg, 93%) that obtains to be white in color.C
22H
25FN
8O
3The accurate mass calculated value 500 18 of S, experimental value 501 1 (MH
+).
Instance 9.207: preparation 3-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-tetramethyleneimine-1-t-butyl formate (compd A 140).
At room temperature the 3-hydroxyl-tetramethyleneimine among the THF (10mL)-1-t-butyl formate (431mg, 2 3mmol) and sodium hydride (92mg, 3 82mmol) mixture are stirred 30min.Then add 4-chloro-1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine (500mg, 1 53mmol) also at room temperature with its stirred overnight.The ethyl acetate extraction product is ended and used to the reaction mixture water.With ethyl acetate layer through MgSO
4Drying concentrates in a vacuum, and produces the solid compd A 140 (495mg, 45%) that is white in color through the flash chromatography purifying.C
21H
24FN
5O
5The accurate mass calculated value 477 15 of S, experimental value 478 2 (MH
+).
Instance 9 208: preparation 3-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base is amino]-tetramethyleneimine-1-t-butyl formate (compd A 141).
To be similar to the instance 9205 described modes solid compd A 141 (723mg, 49%) that obtains to be white in color.C
21H
26N
6O
4The accurate mass calculated value 458.17 of S, experimental value 459 2 (MH
+).
Instance 9209: preparation 3-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base is amino]-tetramethyleneimine-1-isopropyl formate (compd A 142).
At room temperature with the [1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3 among the DMF (500 μ L); 4-d] pyrimidine-4-yl]-tetramethyleneimine-3-base-amine (20mg; 0 048mmol), (20 μ L, 144mmol) mixture stirs 2h for isopropyl chlorocarbonate (72 μ L, 0 52mmol) and triethylamine.Through the HPLC purification reaction deposits yields solid compd A 142 (9mg, 41%) that is white in color.C
20H
23FN
6O
4The accurate mass calculated value 462 15 of S, experimental value 463 3 (MH
+).
Instance 9210: preparation 3-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-tetramethyleneimine-1-t-butyl formate (compd A 156).
To be similar to the instance 9207 described modes solid compd A 156 (758mg, 68%) that obtains to be white in color.C
21H
25FN
5O
5The accurate mass calculated value 459 16 of S, experimental value 460 2 (MH
+).
Instance 9211: preparation { 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-(5-pyridine-2-base-thiophene-2-yl)-ketone (compd A 185).
Prepare the solid compd A 185 that is white in color (5mg, 9%) to be similar to instance 925 described modes.C
27H
24N
6O
4S
2Accurate mass calculated value 560 13, experimental value 561 4 (MH
+).
The general method of chloro-formic ester addition
To be dissolved in the dry DMF (3mL) and referring to the compd B 2 (75mg, 0 17mmol) of instance 102 and TEA (0 34mmol, 2 equivalents) and add in the said solution, then at room temperature it stirred 30min isobutyl chlorocarbonate.Produce the solid compound B-11 (46mg, 57%) that is white in color through HPLC purifying crude product.
1HNMR400MHzCDCl
3δ(ppm)：9.23(s，1H)，8.62(s，1H)，8.55(d，1H)，8?34(d，1H)，8?32(s，1H)，5?65(m，1H)，3?98-3?95(m，2H)，3.90(d，2H)，3.43-3.37(m，2H)，3?31(s，3H)，2?13(m，2H)，2?00-1?93(m，3H)，0?955(d，6H)。C
21H
26N
6O
5The accurate mass calculated value of S is 474 17, LCMS (ESI) m/z 475 4 (M+H
+, 100%).
Instance 102: preparation 9-(6-methylsulfonyl-pyridin-3-yl)-6-(piperidin-4-yl oxygen base)-9H-purine (compd B 2).
Be brown solid compd B 2 (171mg, 95%) to be similar to instance 96 described process preparations.
1H?NMR400MHzCDCl
3δ(ppm)9?41(s，1H)，9?07(s，1H)，8?79(d，1H)；8?70(s，1H)；8?34(d，1H)，5?64?(m，1H)，3?36(s，3H)，3?32(m，2H)，3.23(m，2H)，2.26(m，2H)，2?08(m，2H)。C
16H
18N
6O
3The accurate mass calculated value of S is 374 12, experimental value LCMS (ESI) m/z 375 2 (M+H
+, 100%).
Instance 103: preparation { 4-[9-(6-methylsulfonyl-pyridin-3-yl)-9H-purine-6-base oxygen base]-piperidines-]-1-yl }-pyridin-3-yl-ketone (compd B 3).
Be butteriness solid compd B 3 (47mg, 58%) to be similar to instance 97 described process preparations and to separate.
1HNMR?400MHzCDCl
3δ(ppm)9.23(s，1H)；8.70(m，2H)，8?62(s，1H)，8?55(d，1H)，8?54(d，1H)，7?80(m，1H)；5?76(m，1H)，4?18(bs，1H)，3?79(m，2H)，3?47(m，1H)，3?31(s，3H)；2.25(m，1H)；2.12(m，1H)；2.00(1H)。LCMSC
22H
21N
7O
4S calculated value 479 14, observed value 480 3 (M+H
+, 100%).
Instance 104: preparation 4-[9-(4-methylsulfonyl-phenyl)-9H-purine-6-base oxygen base]-piperidines-1-t-butyl formate (compd B 4)
Form purine-as process.
Step 1: preparation 4-[5-amino-6-(4-methylsulfonyl-phenyl amino)-pyrimidine-4-base oxygen base]-piperidines-1-t-butyl formate.
(647mg 1.3mmol) is dissolved in the ETHYLE ACETATE and then adds 10%Pd/C with 4-[6-(4-methylsulfonyl-phenyl amino)-5-nitro-pyrimidine-4-base oxygen base]-piperidines-1-t-butyl formate under nitrogen.At room temperature mixture is stirred the 4h generation and be brown solid 4-[5-amino-6-(4-methylsulfonyl-phenyl amino)-pyrimidine-4-base oxygen base]-piperidines-1-t-butyl formate (535mg, 89%).
1HNMR(CDCl
3，400MHz)δ1?77-1?67(m，4H)，1?48(s，9H)，3?04(s，3H)，3?31-3?24(m，2H)，3?82(m，2H)，5?32(m，1H)，6?96(s，NH)，7?53(t，NH)，7.70(t，1H)，7.71(d?2H)，8?16(s，1H)。C
21H
29N
5O
5The accurate mass calculated value 463 19 of S, experimental value 464 3 (MH
+).
Step 2: preparation 4-[9-(4-methylsulfonyl-phenyl)-9H-purine-6-base oxygen base]-piperidines-1-t-butyl formate (compd B 4).
With 4-[5-amino-6-(4-methylsulfonyl-phenyl amino)-pyrimidine-4-base oxygen base]-piperidines-1-t-butyl formate (300mg; 0.6mmol) be dissolved in the mixture of triethyl orthoformate (4mL) and diacetyl oxide (4mL), then under 140 ℃, make mixture backflow 15h.End crude product and use ethyl acetate extraction with saturated sodium bicarbonate, then make its dried in vacuum.In acetonitrile/water, be settled out solid and produce and be peachiness solid compd B 4 (205mg, 67%).
1HNMR(CDCl
3，400MHz)δ1?48(s，9H)，1?95-1?91(m，2H)，2?14-2.11(m，2H)，3?12(s，3H)，3?34-3?27(m，2H)，3?94-3?91(m，2H)，5?61(m，1H)，8?06(d，2H)，8.19(d，2H)，8?29(s，1H)，8?61(s，1H)。C
22H
27N
5O
5S accurate mass calculated value 473 17, experimental value 474 3 (MH
+).
Instance 105: preparation 4-[9-(6-methylsulfonyl-pyridin-3-yl)-9H-purine-6-base oxygen base]-piperidines-1-t-butyl formate (compd B 5).
Except with 4-[5-amino-6-(6-methylsulfonyl-pyridin-3-yl amino)-pyrimidine-4-base oxygen base]-piperidines-1-t-butyl formate, prepare and be peachiness solid compd B 5 (502mg, 81%) to be similar to instance 104 described modes.
1H?NMR(CDCl
3，400MHz)δ1?49(s，9H)，1?95-1?91(m，2H)，2?14-2.11(m，2H)，3?31(s，3H)，3?35-3?25?(m，2H)，3?94-3?90(m，2H)，5?61(m，1H)，8?32(s，1H)，8?33(d，1H)，8?55(d，1H)，8?61(s，1H)，9.22(s，1H)。C
21H
26N
6O
5The accurate mass calculated value 474 17 of S, experimental value 475 3 (MH
+).
To be similar to the compound B-26 (75mg, 25%) that instance 104 described modes obtain to be yellow solid.
1HNMR400MHzCDCl
3δ(ppm)8?59(s，1H)；8.26(s，1H)，8?19(d，2H)，8.15(t，1H)，7?98(d，1H)；5?62(m，1H)，3?93-3.81(m，2H)，3?35-3?27(m，2H)，3?14(s，3H)；2.10(m，2H)，1?97-1?92(m，2H)，1?49(s，9H)。LCMS C
22H
26FN
5O
5S calculated value 491 16, observed value 492 3 (M+H
+, 100%).
Instance 11
Instance 111 preparation 4-[3-(4-methylsulfonyl-phenyl)-3H-[1,2,3] triazolo [4,5-d] pyrimidin-7-yl oxygen base]-piperidines-1-t-butyl formates (Compound C 1).
Step 1: preparation 7-chloro-3-(4-methylsulfonyl-phenyl)-3H-[1,2,3] triazolo [4,5-d] pyrimidine
At room temperature (646mg 0937mmol) dropwise adds (6-chloro-5-nitro-pyrimidine-4-yl)-(4-methylsulfonyl-phenyl)-amine aqueous solution in methylene dichloride (8mL) and 50% aqueous acetic acid (6mL) with the Sodium Nitrite in the water (1mL).After being added dropwise to complete, at room temperature with reactant restir 15min.Then organic layer is separated, use water washing, and through anhydrous magnesium sulfate drying.Filter, then in high vacuum, remove volatile matter and produce the product of wanting (205mg, 778%) that is yellow solid.
Step 2: preparation 4-[3-(4-methylsulfonyl-phenyl)-3H-[1,2,3] triazolo [4,5-d] pyrimidin-7-yl oxygen base]-piperidines-1-t-butyl formate (Compound C 1).
Through being similar to instance 91 described processes are obtained to be yellow solid by 7-chloro-3-(4-methylsulfonyl-phenyl)-3H-[1,2,3] triazolo [4,5-d] pyrimidine and 4-hydroxy-piperdine-1-t-butyl formate Compound C 1 (1011mg, 66%).
1HNMR(400MHzDMSO-d
6)δ(ppm)8?92(s，1H)，8.52(d，2H)，8?24(d，2H)，5?68(m，1H)；3?78(m，2H)，3?31(s，3H)，3?26(m，2H)，2.12(m，2H)，1?76(m，2H)，1?42(s，9H)。LCMS (ESI): C
21H
26N
6O
5S calculated value: observed value m/z 475 3 (MH
+, 100%)
Instance 12
Instance 121: preparation 4-[3-(4-methylsulfonyl-phenyl)-isoxazoles are [4,5-d] pyrimidin-7-yl oxygen base also]-piperidines-1-t-butyl formate (Compound D 1).
Step 1: preparation 4-methylsulfonyl-benzyl acid phenenyl ester
CH to 4-methylsulfonyl-benzyl acid (20g, 99 9mmol)
2Cl
2(150mL) solution adds oxalyl chloride (13.1mL, 149 9mmol).Reaction mixture is cooled to 0 ℃ also to be handled with DMF (2mL).With reactant temperature to room temperature and keep 10h.Reactant is concentrated in a vacuum and it is dissolved in CH
2Cl
2(200mL).(105mL 120mmol) then uses Et with phenol down at 0 ℃
3N (16 7mL, 120mmol) processing reaction thing.Stir 7h with reactant temperature to room temperature and with it.Use CH
2Cl
2(500mL) extractive reaction thing is dried and concentrates in a vacuum.The crystalline that is white in color through obtain productive rate 78% from methyl alcohol (200mL) recrystallize is wanted compound 4-methylsulfonyl-benzyl acid phenenyl ester (21.5g).
1HNMR(400Mz，DMSO-d
6)δ8.41(d，J＝7.1，2H)，8?39(d，J＝7?1，2H)，7?55～7?51(m，2H)，7.37-7.35(m，3H)，3?35(s，3H)。LCMS?277?0[M+H]。
Step 2: preparation 1-(4-methylsulfonyl-phenyl)-2-nitro-ethyl ketone.
Under 0 ℃, in DMSO (150mL) suspension-s of potassium tert.-butoxide (24 3g, 217 1mmol), add CH
3NO
2(11 7mL, 217.1mmol).After stirring 1h, and adding a 4-methylsulfonyl-benzyl acid phenenyl ester under 0 ℃ (200g, 72.4mmol).With reactant temperature to room temperature and stir 5h.Reactant is poured in the frozen water (200mL) and then added urea (2 17g, 36 2mmol).Under 0 ℃, reactant is acidified to pH=～5 with 50MHCl.Reactant is added in the entry (1L) and stirs 1h.Light yellow solid is filtered and the dry compound of wanting (13 2g, 75.2%) that produces under vacuum.
1H?NMR(400Mz，DMSO-d
6)δ8?19(m，4H)，6?63(s，2H)，3?35(s，3H)。LCMS?244?5[M+H]。
Step 3: preparation 1-(4-methylsulfonyl-phenyl)-2-nitro-ethyl ketone oxime.
At room temperature the ethanolic soln to 1-(4-methylsulfonyl-phenyl)-2-nitro-ethyl ketone (12 5g, 51 4mmol) adds NH
2OHHCl (3 57g, 51 4mmol) and acetate (33mL).Make reactant backflow 3h and it is cooled to room temperature.Reactant is concentrated in a vacuum and extract with ETHYLE ACETATE (200mL).Make reactant concentrate produce crude product, said crude product in sherwood oil/hexane (1/3) as white crystal recrystallize (10 3g, 83 4%).
1HNMR(400Mz，DMSO-d
6)δ12?81(s，1H)，8?03(m，4H)，5?93(s，2H)，3?28(s，3H)。LCMS?259?2[M+H]。
Step 4: preparation 3-(4-methylsulfonyl-phenyl)-4-nitro-isoxazoles-5-ethyl formate.
(10 0g, 38.7mmol) solution adds chloroethyl oxalic acid ethyl ester (4 29mL, 38 7mmol) to 1-(4-methylsulfonyl-phenyl)-2-nitro-ethyl ketone oxime in ether (100mL) and THF (50mL) at ambient temperature.Reactant is stirred 16h and it is concentrated in a vacuum.With ether (100mL) debris.Solids filtered is also washed with ether.With compound dissolution in THF (50mL) and ether (100mL) and use Et
3N (～15mL) THF (10mL) solution-treated.Terminal point through the TLC assaying reaction.Pour reactant into H
2Among the O (200mL).Make organic layer through MgSO
4Drying also makes its concentrated generation be the crude product that solid is wanted compound.Make compound recrystallize in ethyl acetate/hexane (50mL/150mL) produce the compound of wanting (62g, 47%) that is pale yellow crystals.
1HNMR(400Mz，DMSO)δ8.40(d，J＝7.1，2H)，8?21(d，J＝7?1，2H)，3?35(s，3H)，2.63(q，2H)，1?05(t，3H)。
Step 5: preparation 4-amino-3-(4-methylsulfonyl-phenyl)-isoxazoles-5-ethyl formate.
At room temperature make 3-(4-methylsulfonyl-phenyl)-4-nitro-isoxazoles-5-ethyl formate (62g) be suspended in saturated NH
4Also handle among the Cl (100mL) with Zn (10.0g).Reactant is stirred 3h and adds ETHYLE ACETATE (100mL).After stirring 1h zinc is leached.ETHYLE ACETATE is absorbed and uses H
2The O washing is through MgSO
4Drying also concentrates generation crude product (43g, 77%) under vacuum.Make product crystallization in ethyl acetate/hexane (1/3) produce the compound of wanting.LCMS?311?1[M+H]。
Step 6: preparation 4-amino-3-(4-methylsulfonyl-phenyl)-isoxazoles-5-benzoic acid amides.
At room temperature (40g, methyl alcohol 12.9mmol) (50mL) and THF (50mL) solution add NH to 4-amino-3-(4-methylsulfonyl-phenyl)-isoxazoles-5-ethyl formate
4OH solution (100mL).Reactant is stirred 24h.Filtering-depositing is also used H
2O (100mL) washing.Make the compound dried in vacuum produce crude product, said crude product is used for next step without being further purified.LCMS?282?1[M+H]。
Step 7: preparation 3-(4-methylsulfonyl-phenyl)-isoxazoles are [4,5-d] pyrimidin-7-ol also.
At ambient temperature to the CH (OEt) of 4-amino-3-(4-methylsulfonyl-phenyl)-isoxazoles-5-benzoic acid amides (2.5g, 8 9mmol)
3(30mL) suspension-s adds diacetyl oxide (10mL).With reaction mass heated to refluxing 5h and it is cooled to room temperature.To react and concentrate in a vacuum and be poured in the water (50mL).With ETHYLE ACETATE (50mL) extraction organic materials, make it through MgSO
4Dry and concentrated in a vacuum.Crude product is used for next step without being further purified.LCMS?292?0[M+H]。
Step 8: preparation 7-chloro-3-(4-methylsulfonyl-phenyl)-isoxazoles are [4,5-d] pyrimidine also.
(0 5g 1.7mmol) is suspended in POCl with 3-(4-methylsulfonyl-phenyl)-isoxazoles [4,5-d] pyrimidin-7-ol
3(10mL) and make its backflow 12h.With careful the pouring in the ice and filtering-depositing of reactant.Be dissolved in the ETHYLE ACETATE solid and at SiO
2In produce the compound of being wanted (0.42g, 80 1%) with 30% ETHYLE ACETATE purifying in the hexane.
Step 9: preparation 4-[3-(4-methylsulfonyl-phenyl)-isoxazoles are [4,5-d] pyrimidin-7-yl oxygen base also]-piperidines-1-t-butyl formate (Compound D 1).
At ambient temperature 4-hydroxy-piperdine-1-t-butyl formate (0.1g, 0 49mmol) is dissolved among the anhydrous THF (5mL) and with NaH, 60% oily dispersion liquid (20mg, 0 49mmol) and handles.After stirring 10min, add also [4,5-d] pyrimidine (0 15g, 0 49mmol) of 7-chloro-3-(4-methylsulfonyl-phenyl)-isoxazoles.Reactant is stirred 3h and it is concentrated in a vacuum.Produce 4-[3-(4-methylsulfonyl-phenyl)-isoxazoles are [4,5-d] pyrimidin-7-yl oxygen base also]-piperidines-1-t-butyl formate (0 14g, 61%) through tubing string chromatography (ETHYLE ACETATE and hexane (1/1)) purifying resistates.
1HNMR(400Mz，DMSO-d
6)δ8.51(s，1H)，8?42(d，J＝7?1，2H)，8?34(d，y＝7.1，2H)，4?11～3?83(m，4H)，3.52(m，1H)，3?26(s，3H)，1?41～1?22(m，4H)。LCMS?475?3[M+H]。
Instance 12 2: preparation 4-({ ethyl-[3-(4-methylsulfonyl-phenyl)-isoxazoles are [4,5-d] pyrimidin-7-yl also]-amino }-methyl)-piperidines-1-t-butyl formate (Compound D 2).
At ambient temperature 4-ethylamino methyl-piperidines-1-t-butyl formate (0 12g, 0 49mmol) is dissolved among the anhydrous THF (5mL) and with NaH, 60% oily dispersion liquid (20mg, 0 49mmol) and handles.After stirring 10min, add also [4,5-d] pyrimidine (0 15g, 0 49mmol) of 7-chloro-3-(4-methylsulfonyl-phenyl)-isoxazoles.Reactant is stirred 3h and it is concentrated in a vacuum.Make resistates stand SiO
2(ETHYLE ACETATE and hexane (1/1)) produces Compound D 2 (0 82g, 61%).
1HNMR(400Mz，DMSO-d
6)5?849(s，1H)，8?41(d，J＝7?1，2H)，8?34(d，J＝7?1，2H)，4?10～3?74(m，7H)，3?52(m，1H)，3?25(t，3H)，1.41～1?22(m，4H)。LCMS?516?3[M+H]。
Instance 123: preparation 4-[3-(4-methylsulfonyl-phenyl)-isoxazoles are [4,5-d] pyrimidin-7-yl sulfenyl also]-piperidines-1-t-butyl formate (compound d3).
With 7-chloro-3-(4-methylsulfonyl-phenyl)-isoxazoles also [4; 5-d] pyrimidine (0.19mmol; 60mg), 4-sulfydryl-piperidines-1-t-butyl formate (0.25mmol, 54mg) and salt of wormwood (0 28mmol 35mg) is dissolved among the DMF (10mL) and at room temperature it is stirred 90min.Monitor said process by thin layer chromatography and LCMS.The water stopped reaction is also wanted compound with ethyl acetate extraction.Evaporate organic layer in the vacuum.Produce the solid compound d3 (40mg, 35%) that is white in color through the HPLC purifying.
1HNMR(400Mz，CDCl
3)8?903(s，1H)，8?71(d，2H)；8.15(d，2H)，4.44(h，1H)，4?02(m，2H)，3.22(m，2H)，3?13(s，3H)，2?19(m，2H)，1?82(m，2H)，1?47(s，9H)。LCMS(ESI)，m/z491?1(MH+，100％)。
Instance 124: preparation 4-[3-(4-methylsulfonyl-phenyl)-isoxazoles are [4,5-d] pyrimidin-7-yl oxygen base also]-piperidines-1-isopropyl formate (Compound D 4).
[3-(4-methylsulfonyl-phenyl)-isoxazoles are [4,5-d] pyrimidin-7-yl oxygen base also]-(12g 253mmol) is dissolved in CH to piperidines-1-t-butyl formate with 4-
2Cl
2Be cooled to 0 ℃ (5mL) and with it.Stir 5h with reactant temperature to room temperature and with it.Reactant is concentrated in a vacuum and it is dissolved in the methyl alcohol (10mL).With sedimentation and filtration and the dry hydrochloride that produces amine.Under 0 ℃ with said salt at CH
2Cl
2Stir and use Et (20mL)
3N and chloroformic acid chlorine isopropyl ester are handled.Pour reactant into H after stirring 5h
2Among the O (20mL).Use CH
2Cl
2(30mL) extracting of organic compounds and use brine wash.With ethyl acetate layer through MgSO
4Dry and concentrated in a vacuum.Through SiO
2The purifying resistates produces Compound D 4 (970mg, 83 4%).
1HNMR(400Mz，DMSO-d
6)δ8?50(s，1H)，8?41(d，7＝7?0，2H)，8.35(d，J＝7.0，2H)，4?11～3.83(m，4H)，3?52(m，1H)，3?47(m，1H)，3.25(d，6H)，1?41～1?22(m，4H)。LCMS?461?6[M+H]。
Instance 13 1 preparation 4-[8-{4-bromo-2-fluoro-phenyl)-quinolyl-4 oxygen base]-piperidines-1-isopropyl formate (compound F 17-hydroxy-corticosterone 5).
Step 1: preparation 2-[(2-iodo-phenyl amino)-methylene radical]-ethyl malonate.
2-Iodoaniline (50g, 228 3mmol) and 2-oxyethyl group methylene radical-ethyl malonate (50mL, 251 1mmol) mixed be incorporated under 110 ℃ solution stirring 3h.With crude product be dissolved in the methylene dichloride and through the silicon-dioxide plug with its purifying.Remove solvent with ethyl acetate/hexane (10-50%) elution product and decompression and produce 2-[(2-iodo-phenyl amino)-methylene radical]-ethyl malonate (81 4g, 91.6%) that is the beige powder.
1H?NMR(CDCl
3，400MHz)5?149(t，3H)，1?54(t，3H)，4?40(q，2H)，4.52(q，2H)，7.01-7?05(m，1H)，7?36-7.39(m，1H)，7?52-7?56(m，1H)，8?59(d，1H)。C
14H
16INO
4Accurate mass calculated value 389 01, experimental value 390 1 (MH
+).
Step 2: preparation 8-iodo-4-ketone group-1,4-dihydro-quinoline-3-ethyl formate.
In 2 mouthfuls of round-bottomed flasks (250mL), adding phenylate (60mL) refluxes it on mantel pick-up., it adds tosic acid (0.140g) when coming to life.2-[(2-iodo-phenyl amino)-methylene radical]-ethyl malonate is dissolved in the phenylate (20mL) and with mixture and pours in the boiling solvent.Make mixture backflow 3h.Crude product is transferred to bequer and makes it be cooled to room temperature.Add hexane (600mL) and observe to such an extent that precipitate.Mixture is stirred 5min, follow solids filtered and thoroughly wash the 8-iodo-4-ketone group-1 that generation is light gray solid, 4-dihydro-quinoline-3-ethyl formate (2g, 46%) with hexane.
1H?NMR(DMSO-d
6，400MHz)δ1.43(t，3H)，4.39(q，2H)，7?36(t1H)，8?32(d，1H)，8?37(d，1H)，8.63(s，1H)，11?4(s，1H)。C
12H
10INO
3Accurate mass calculated value 342.97, experimental value 343 9 (MH
+).
Step 3: preparation 8-iodo-4-ketone group-1,4-dihydro-quinoline-3-formic acid.
With 8-iodo-4-ketone group-1, (2g 5.83mmol) is suspended among the 10%NaOH in the water (20mL) 4-dihydro-quinoline-3-ethyl formate.Mixture is stirred 1h under refluxing.Crude product is cooled to room temperature also with dense HCl acidifying.Leach solid and water its thorough washing generation is little peachiness solid 8-iodo-4-ketone group-1,4-dihydro-quinoline-3-formic acid (1 5g, 816%).
1HNMR(DMSO-d
6，400MHz)δ7?04(t，1H)，8?12-8?16(m，2H)，8?71(s，1H)。C
10H
6INO
3The accurate mass calculated value 314 94 of S, experimental value 316 (MH
+).
Step 4: preparation 8-iodo-1H-quinoline-4-ketone
With 8-iodo-4-ketone group-1,4-dihydro-quinoline-3-formic acid (1569g, 498mmol) be suspended in the phenylate (40mL) and with mixture heating up to boiling.Behind the 30min, show the reaction completion through LCMS.Crude product is transferred to bequer and makes it be cooled to room temperature.Add hexane (500mL) and mixture is stirred 10min.Through the filtered and recycled solid, produce the 8-iodo-1H-quinoline-4-ketone (44g, 23%) that is little brown solid with its thorough washing and through the HPLC purifying with hexane.
1H?NMR(DMSO-d
6，400MHz)5614(d，1H)，7?09(t，1H)，7?88(d，1H)，8?08(dd，1H)，8?16(dd，1H)。C
9H
6The accurate mass calculated value 270.95 of INO, experimental value 271.8 (MH
+).
Step 5: preparation 4-chloro-8-iodo-quinoline.
(3.36g 8.72mmol) is suspended in POCl with 8-iodo-1H-quinoline-4-ketone
3(8mL, 87 2mmol) also add catalytic amount dry DMF (672uL).Make mixture backflow 1h.Hot crude product is stirred until ice thawing fully extremely on ice and with mixture.With the solid filtering, water thoroughly washs and it is kept at the 4-chloro-8-iodo-quinoline (2.47g, 98%) that generation overnight in the vacuum chamber is little gray solid.
1HNMR(DMSO-d
6，400MHz)δ7.45(t，1H)，7.81(d，1H)，8?19(dd，1H)，8.45(dd，1H)，8?87(d，1H)。C
9H
5The accurate mass calculated value 288 92 of ClIN, experimental value 289 9 (MH
+).
Step 6: preparation 8-(4-bromo-2-fluoro-phenyl)-4-chloro-quinoline.
At N
2(14 5mg, 0.5mmol) (57mg, 0.05mmol) solution adds the 0.5MTHF solution of 2-fluoro-4-bromine zinc iodide (1mL) to 4-chloro-8-iodo-quinoline in THF (1mL) with four (triphenylphosphine) palladiums down.Under 65 ℃, reaction mixture is heated overnight.Use CH
2Cl
2Dilution gained mixture also passes through injection filter and filters.To filtrate to concentrate and pass through tubing string chromatography (15%EtOAc/ hexane) purifying and produce 8-(4-bromo-2-fluoro-phenyl)-4-chloro-quinoline.
1HNMR (CDCl
3, 400MHz) δ 7.41 (m, 3H), 7 52 (d, 1H), 7 74 (m, 2H), 8 34 (m, 1H), 8 78 (d, 1H) C
15H
8The accurate mass calculated value 334 95 of BrClFN, experimental value 336 2 (MH
+).
Step 7: preparation 4-[8-(4-bromo-2-fluoro-phenyl)-quinolyl-4 oxygen base]-piperidines-1-isopropyl formate (compound F 17-hydroxy-corticosterone 5).
Is being furnished with N
2(in the MO 60%, 40mg is 1mmol) with 4-hydroxy-piperdine-1-tetryl formate (37mg, 0 2mmol) for the stirring rod, NaH of packing in the 10mL reaction flask of inlet dividing plate.THF (anhydrous, 1 2mL) is added in the mixture.At room temperature with gained suspension-s stir about 30min.Then add a 8-(4-bromo-2-fluoro-phenyl)-4-chloro-quinoline (1g, 0 5mmol).Under 65 ℃ at N
2Down with mixture stirred overnight and gained slurries little band yellow that becomes.With CH
2Cl
2Add in the slurries and filtration.Make filtrating concentrate and produce crude product in a vacuum.Be the beige solid through the generation of tubing string purification by chromatography and want compound F 17-hydroxy-corticosterone 5.
1HNMR(CDCl
3，400MHz)δ1.27(d，6H)，1.97(m，2H)，2.05(m，2H)，3?59(m，2H)，3.75(m，2H)，4?84(m，1H)，4?94(m，1H)，6?76(d，1H)，7?39(m，3H)，7?56(t，1H)，7.67(d，1H)，8?31(d，1H)，8?74(d，1H)。C
24H
24BrFN
2O
3Accurate mass calculated value 486 10, experimental value 487 2 (MH
+).
Instance 13 2: preparation 4-[8-(4-methyl sulfenyl-phenyl)-quinolyl-4 oxygen base]-piperidines-1-isopropyl formate (compound F 17-hydroxy-corticosterone 2).
Step 1: preparation 4-(8-chloro-quinolyl-4 oxygen base)-piperidines-1-isopropyl formate.
Is being furnished with N
2Pack in the 50mL round-bottomed flask of inlet dividing plate stirring rod, NaH (60%, 1 1g in the MO, 30mmol) with 4-hydroxy-piperdine 5-tetryl formate (0 93g, 5mmol).With THF (anhydrous, 20mL) add in the mixture.At room temperature with gained suspension-s stir about 30min.Then add portion 4,8-two chloro-quinoline (1g, 0 5mmol).Under 80 ℃ at N
2Down with mixture stirred overnight and gained slurries little band yellow that becomes.With CH
2Cl
2Add in the slurries and filtration.Make filtrating concentrate and produce crude product in a vacuum.Be beige solid 4-(8-chloro-quinolyl-4 oxygen base)-piperidines-1-isopropyl formate through the generation of tubing string purification by chromatography.
1HNMR(CDCl
3，400MHz)δ1.26(d，6H)，1?97(m，2H)，2?05(m，2H)，3?58(m，2H)，373(m，2H)，4.82(m，1H)，4?94(m，1H)，6?81(d，1H)，7?42(t，1H)，7?84(d，1H)，8?16(d，1H)，8?87(d，1H)。C
18H
21ClN
2O
3Accurate mass calculated value 348 12, experimental value 349 2 (MH
+).
Step 2: preparation 4-[8-(4-methyl sulfenyl-phenyl)-quinolyl-4 oxygen base]-piperidines-1-isopropyl formate.
Be furnished with reflux exchanger and N
2Stirring rod, 4-(8-chloro-quinolyl-4 oxygen base)-piperidines-1-isopropyl formate (198mg pack in the 25mL round-bottomed flask of inlet dividing plate; 0.57mmol), 4-methylthio phenyl ylboronic acid (287mg; 1.7mmol), wantonly (triphenylphosphine) palladiums (98mg, 0.085mmol), 2M yellow soda ash (0.6mL) and toluene (4mL).At N
2Under make mixture backflow 36h.Dilute the gained mixture and use H with ETHYLE ACETATE
2The O extraction.Make the dry and concentrated crude product that produces of organic extract.Produce the product of wanting through tubing string chromatography (50%EtOAc/ hexane) and preparation HPLC purifying crude product.
1H?NMR(CDCl
3，400MHz)δ1?27(d，6H)，2.04(m，2H)，2?17(m，2H)，2?55(s，3H)，3?59(m，2H)，3.83(m，2H)，4?97(m，1H)，5?09(m，1H)，7?14(s，1H)，7.41(m，4H)，7?81(t，1H)，7?90(d，1H)，8?38(d，1H)，9.11(s，1H)。C
25H
28N
2O
3The accurate mass calculated value 436 18 of S, experimental value 437 2 (MH
+).
Instance 13.3: preparation 4-[8-(4-methylsulfonyl-phenyl)-quinolyl-4 oxygen base]-piperidines-1-isopropyl formate (compound F 17-hydroxy-corticosterone 3).
Stirring rod and CH pack in the 25mL round-bottomed flask in being immersed in ice bath
2Cl
2Compound F 17-hydroxy-corticosterone 2 (5mL) (16mg, 0 037mmol).Under 0 ℃, add and be dissolved in CH
2Cl
2MCPBA (1mL) (19mg, 0 081mmol) solution.Under 0 ℃, mixture is stirred 30min.Add sodium sulfite solution.Organic phase is separated the dry and concentrated crude product that produces.Through HPLC purifying crude product.
1H?NMR(CDCl
3，400MHz)δ1.29(d，6H)，2?04(m，2H)，220(m，2H)，3.16(s，3H)，3.59(m，2H)，3.85(m，2H)，4?97(m，1H)，5?14(m，1H)，7.23(s，1H)，7.66(d，2H)，7?92(m，2H)，8?12(d，2H)，8?48(d，1H)，9.08(d，1H)。C
25H
28N
2O
5The accurate mass calculated value 468.17 of S, experimental value 469 2 (MH
+).
Instance 134: preparation 4-[8-(4-isopropoxy-phenyl)-quinolyl-4 oxygen base]-piperidines-1-isopropyl formate (compound F 17-hydroxy-corticosterone 4).
Stirring rod, 4-(8-chloro-quinolyl-4 oxygen base)-piperidines-1-isopropyl formate (200mg pack in the 25mL round-bottomed flask of being furnished with reflux exchanger and N2 inlet dividing plate; 0 57mmol), 4-isopropoxy benzene ylboronic acid (304mg, 1 7mmol), 2M yellow soda ash (0 6mL) and toluene (4mL).Mixture was outgased several minutes.Wantonly (triphenylphosphine) palladium (98mg, 0 085mmol) adds in the said mixture.Make reaction mixture at N
2Refluxed is overnight.Dilute the gained mixture and use H with ETHYLE ACETATE
2The O extraction.Make the dry and concentrated crude product that produces of organic extract.Produce the product of wanting through tubing string chromatography (50%EtOAc/ hexane) and preparation HPLC purifying crude product.
1H?NMR(CDCl
3，400MHz)δ1?28(d，6H)，1?39(d，6H)，2?03(m，2H)，2?17(m，2H)，3?59(m，2H)，3?85(m，2H)，4?63(m，1H)，4?97(m，1H)，5?12(m，1H)，7?04(s，1H)，7?22(d，1H)，7?37(d，2H)，7?81(t，1H)，7?90(d，1H)，8?36(d，1H)，9?06(d，1H)。C
27H
32N
2O
4Accurate mass calculated value 448.24, experimental value 449 4 (MH
+).
Instance 14
RUP3 dose response scheme in the melanocyte
According to Potenza, M N and Lerner, M.R, in Pigment Cell Research, the 5th volume, 372-378,1992 reports are retained in melanocyte in the nutrient solution and pass through electroporation with RUP3 expression vector (pCMV) transfection.Behind the electroporation, with transfectional cell be applied to be used in 96 orifice plates check.Then make cell growth 48h make it recover and reach maximum expression of receptor level from electroporation process.
Checking the same day, replace the growth medium on the cell with the serum-free damping fluid that contains the 10nM melatonon.Melatonon is through the endogenous G in the melanocyte
1Coupling GPCR reduces cAMP level in the cell.In response to the cAMP level that reduces, melanocyte is transferred to cell centre with its pigment.Its net effect is significantly to reduce the light absorption ratio reading of cell monolayer in the hole of under 600-650nM, measuring.
After in melatonon, cultivating 1h, the cytopigment complete aggegation that becomes.Collect baseline light absorption ratio reading in this.Then add the test compounds of serial dilution in the entering plate and stimulate the compound of RUP3 to make that the cAMP level increases in the cell.Increase in response to these cAMP levels, it is peripheral that melanocyte shifts back cell with its pigment.After one hour, being excited the pigment of cell disperses fully.The cell monolayer of dispersion state absorbs the light of more 600-650nm scopes.The specific absorption of comparing with the baseline reading that measures increases and allows with the degree of being excited of acceptor quantitatively and plot dose-response curve.
Compound with the above instance of melanocyte check screening.Table 10 has been showed the corresponding EC with it of representative compound
50Value:
Table 10
| Compound | RUP3(EC 50)(nM) |
| A5 | 12?7 |
| B5 | 59?1 |
| C1 | 13?0 |
EC in other compound exhibits melanocyte check in the instance
50Active in about 10 μ M.Various embodiments of the present invention or can relate to those limitedly and compare with corticotropin releasing factor(CRF)-1 (CRF-1) acceptor and show about 100 times or be bonded to the compound of RUP3 more by force; At Expert Opin Ther Patents 2002,12 (11), can find the nearest summary of CRF-1 compound among the 1619-1630, it is incorporated herein by reference fully.
Instance 15
Ingestion of food research
With male ZDF (Zucker mellitus fat) the rat independence administration of chemotypes different on two structures of showing RUP3 receptor agonism property to body weight 350g-400g.Every day with mediator (100%PEG400), first compound (30mg/kg, 100mg/kg) or second compound (10mg/kg is 30mg/kg) with the oral tube feed rat of the volume of 3ml/kg.Monitoring every day and record body weight and ingestion of food.Body weight (g) and the accumulation ingestion of food (g) of following table 11 explanation administrations after 7 days and 14 days.
Table 11
Those one of ordinary skill in the art will recognize and can carry out various corrections, add, replace and change and not deviate from spirit of the present invention and therefore think that it is in category of the present invention illustrative example mentioned above.All documents of preceding text reference include, but is not limited to publish open case and temporary patent application case and formal patent application case, all are incorporated herein by reference.
Claims (52)
1. the hydrate of a compound or solvolyte, said compound has following molecular formula:
Wherein:
A and B independently are randomly by 1 to 4 substituted C of substituting group that is selected from following group separately
1-3Alkylidene group: C
1-3Alkyl, C
1-4Alkoxyl group, carboxyl, cyanic acid, C
1-3Alkylhalide group and halogen;
D is CR
1R
2Or N-R
2, R wherein
1Be selected from H, C
1-8Alkyl, C
1-4Alkoxyl group, halogen and hydroxyl;
E is N, C or CR
3, R wherein
3Be H or C
1-8Alkyl;
When E is N or CR
3The time
Be singly-bound;
is two keys when E is C;
K is C
3-6Cycloalkylidene or C
1-3Alkylidene group, it is randomly replaced by 1 to 4 substituting group that is selected from following group separately: C
1-3Alkyl, C
1-4Alkoxyl group, carboxyl, cyanic acid, C
1-3Alkylhalide group and halogen;
Or K is a key;
Q is O, S, S (O) or S (O)
2,
R
5And R
10Independently be selected from separately: H and CH
3,
Ar
1For separately randomly by R
13, R
14, R
15, R
16And R
17Substituted phenyl or pyridyl;
Wherein
R
13Be selected from: C
1-5Acyl group, C
1-6Acyl group sulfoamido, C
1-5Acyloxy, C
2-6Thiazolinyl, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkylamino, C
1-6Alkyl carboxamide groups, C
1-4Alkylthio carboxamide groups, C
2-6Alkynyl, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, C
1-4Alkylthio urea groups, C
1-4Alkyl urea groups, amino, aryl sulfonyl, carbamyl imino-, carbonyl-C
1-6-alkoxyl group, carboxamide groups, carboxyl, cyanic acid, C
3-7Naphthenic base, C
3-7Cycloalkyloxy, C
2-6Dialkyl amido, C
2-6Dialkyl group carboxamide groups, C
2-6Two alkylthio carboxamide groups, guanidine radicals, halogen, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, C
1-4Alkylhalide group sulfinyl, C
1-4Alkylhalide group alkylsulfonyl, C
1-4Alkyl halide sulfenyl, heterocyclic radical, heterocyclic radical-oxygen base, heterocyclic radical alkylsulfonyl, heterocyclic radical-carbonyl, heteroaryl, heteroaryl carbonyl, hydroxyl, nitro, C
4-7Ketone group-naphthenic base, phenoxy, phenyl, sulfoamido ,-SO
3H and-SH,
And wherein said C
1-5Acyl group, C
1-6Acyl group sulfoamido, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkylamino, C
1-6Alkylsulfonamido, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, aryl sulfonyl, carbamyl imino-, C
2-6Dialkyl amido, heterocyclic radical, heterocyclic radical-carbonyl, heteroaryl, phenoxy and phenyl are randomly replaced by 1 to 5 substituting group that independently is selected from following group: C
1-5Acyl group, C
1-5Acyloxy, C
2-6Thiazolinyl, C
1-4Alkoxyl group, C
1-7Alkyl, C
1-4Alkylamino, C
1-4Alkyl carboxamide groups, C
2-6Alkynyl, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, C
1-4Alkyl urea groups, carbonyl-C
1-6-alkoxyl group, carboxamide groups, carboxyl, cyanic acid, C
3-7Naphthenic base, C
3-7Cycloalkyloxy, C
2-6Dialkyl amido, C
2-6Dialkyl group carboxamide groups, halogen, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, C
1-4Alkylhalide group sulfinyl, C
1-4Alkylhalide group alkylsulfonyl, C
1-4Alkyl halide sulfenyl, heteroaryl, heterocyclic radical, hydroxyl, nitro, phenyl and phosphonato,
And wherein said C
1-7Alkyl and C
1-4The alkyl carboxamide groups randomly is selected from C by 1 to 5 separately
1-4The substituting group of alkoxyl group and hydroxyl replaces;
Or: R
13Be formula (A) group:
Wherein:
" p " and " r " independently is 0,1,2 or 3, and
R
18Be H, C
1-5Acyl group, C
2-6Thiazolinyl, C
1-8Alkyl, C
1-4Alkyl carboxamide groups, C
2-6Alkynyl, C
1-4Alkylsulfonamido, carbonyl-C
1-6-alkoxyl group, carboxamide groups, carboxyl, cyanic acid, C
3-7Naphthenic base, C
2-6Dialkyl group carboxamide groups, halogen, heteroaryl or phenyl, and wherein said heteroaryl or phenyl are randomly replaced by 1 to 5 substituting group that independently is selected from following group: C
1-4Alkoxyl group, amino, C
1-4Alkylamino, C
2-6Alkynyl, C
2-8Dialkyl amido, halogen, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group and hydroxyl;
R
14, R
15, R
16And R
17Independently be selected from separately: H, C
1-5Acyl group, C
1-5Acyloxy, C
2-6Thiazolinyl, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkyl carboxamide groups, C
2-6Alkynyl, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, C
1-4Alkyl urea groups, carbonyl-C
1-6-alkoxyl group, carboxamide groups, carboxyl, cyanic acid, C
3-7Naphthenic base, C
2-6Dialkyl group carboxamide groups, halogen, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, C
1-4Alkylhalide group sulfinyl, C
1-4Alkylhalide group alkylsulfonyl, C
1-4Alkyl halide sulfenyl, hydroxyl and nitro;
Or two adjacent R
14, R
15, R
16, and R
17The atom that is connected with them can form and Ar jointly
1Condensed 5,6 or 7 yuan of naphthenic base, cycloalkenyl group or heterocyclic radicals, wherein said 5,6 or 7 yuan of groups are replaced by halogen, and
R
2Be selected from: C
1-8Alkyl, C
2-6Alkynyl, amino, aryl, carboxamide groups, carboxyl, cyanic acid, C
3-6-naphthenic base, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, halogen, heteroaryl and hydroxyl;
And wherein said C
1-8Alkyl, aryl and heteroaryl are randomly replaced by 1 to 5 substituting group that is selected from following group separately: C
1-5Acyl group, C
1-5Acyloxy, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkylamino, C
1-4Alkyl carboxamide groups, C
1-4Alkylthio carboxamide groups, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, C
1-4Alkylthio urea groups, C
1-4Alkyl urea groups, amino, carbonyl-C
1-6-alkoxyl group, carboxamide groups, carboxyl, cyanic acid, C
3-6-naphthenic base, C
3-6-naphthenic base-C
1-3-assorted alkylidene group, C
2-8Dialkyl amido, C
2-6Dialkyl group carboxamide groups, C
2-6Two alkylthio carboxamide groups, C
2-6Dialkyl group sulfoamido, C
1-4Alkylthio urea groups, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, C
1-4Alkylhalide group sulfinyl, C
1-4Alkylhalide group alkylsulfonyl, C
1-4Alkyl halide sulfenyl, halogen, heterocyclic radical, hydroxyl, hydroxyl amino and nitro;
Or: R
2For-Ar
2-Ar
3, Ar wherein
2And Ar
3Independent of separately randomly being selected from by the substituted aryl of the substituting group of following group or heteroaryl .H, C separately by 1 to 5
1-5Acyl group, C
1-5Acyloxy, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkyl carboxamide groups, C
1-4Alkylthio carboxamide groups, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, amino, C
1-4Alkylamino, carbonyl-C
1-6-alkoxyl group, carboxamide groups, carboxyl, cyanic acid, C
3-6-naphthenic base, C
2-8Dialkyl amido, C
2-6Dialkyl group carboxamide groups, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, halogen, hydroxyl and nitro;
Or R
2Be formula (B) group:
Wherein
R
19Be H, C
1-8Alkyl, C
3-7Naphthenic base, aryl, heteroaryl or OR
21And
R
20Be F, Cl, Br, CN or NR
22R
23: wherein
R
21Be H, C
1-8Alkyl or C
3-7Naphthenic base, and
R
22And R
23Independent is H, C
1-8Alkyl, C
3-7Naphthenic base, aryl or heteroaryl; Or: R
2Be formula (C) group
Wherein
G does
(i) when D be CR
2R
3The time, G is :-C (O)-,-C (O) NR
25-,-NR
25C (O)-,-NR
25-,-NR
25C (O) O-,-OC (O) NR
25-,-CR
25R
26NR
27C (O)-,-CR
25R
26C (O) NR
27-,-C (O) O-, OC (O) ,-C (S)-,-C (S) NR
25-,-C (S) O-,-OC (S)-,-CR
25R
26-,-O-,-S-,-S (O)-,-S (O)
2-or a key; Or
(ii) working as D is NR
2The time, G is :-CR
25R
26C (O)-,-C (O) ,-CR
25R
26C (O) NR
27-,-C (O) NR
25-,-C (O) O-,-C (S)-,-C (S) NR
25-,-C (S) O-,-CR
25R
26-,-S (O)
2-or a key;
R wherein
25, R
26And R
27Independent separately is H or C
1-8Alkyl, and
R
24For separately randomly by 1 to 5 substituted C of substituting group that is selected from following group
1-8Alkyl, C
3-7Naphthenic base, phenyl, heteroaryl or heterocyclic radical: C
1-5Acyl group, C
1-5Acyloxy, C
2-6Thiazolinyl, C
1-4Alkoxyl group, C
1-7Alkyl, C
1-4Alkylamino, C
1-4Alkyl carboxamide groups, C
1-4Alkylthio carboxamide groups, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, C
1-4Alkylthio urea groups, C
1-4Alkyl urea groups, amino, carbonyl-C
1-6-alkoxyl group, carboxamide groups, carboxyl, cyanic acid, C
3-7Naphthenic base, C
2-8Dialkyl amido, C
2-6Dialkyl group carboxamide groups, C
2-6Two alkylthio carboxamide groups, C
2-6Dialkyl group sulfoamido, C
1-4Alkylthio urea groups, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, C
1-4Alkylhalide group sulfinyl, C
1-4Alkylhalide group alkylsulfonyl, C
1-4Alkyl halide sulfenyl, halogen, heteroaryl, heterocyclic radical, hydroxyl, hydroxyl amino, nitro, phenyl, phenoxy and-SO
3H,
Wherein said C
1-4Alkoxyl group, C
1-7Alkyl, C
1-4Alkylamino, heteroaryl, phenyl and phenoxy are randomly replaced by 1 to 5 substituting group that is selected from following group separately: C
1-5Acyl group, C
1-5Acyloxy, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkylamino, C
1-4Alkyl carboxamide groups, C
1-4Alkylthio carboxamide groups, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, C
1-4Alkylthio urea groups, C
1-4Alkyl urea groups, amino, carbonyl-C
1-6-alkoxyl group, carboxamide groups, carboxyl, cyanic acid, C
3-7Naphthenic base, C
2-8Dialkyl amido, C
2-6Dialkyl group carboxamide groups, C
2-6Two alkylthio carboxamide groups, C
2-6Dialkyl group sulfoamido, C
1-4Alkylthio urea groups, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, C
1-4Alkylhalide group sulfinyl, C
1-4Alkylhalide group alkylsulfonyl, C
1-4Alkyl halide sulfenyl, halogen, heterocyclic radical, hydroxyl, hydroxyl amino, nitro and phenyl, wherein:
" aryl " expression contains the fragrant cyclic group of 6 to 10 ring carbon atoms,
" heteroaryl " expression aromatic nucleus system, said aromatic nucleus system is selected from heteroatoms metathetical monocycle, two condensed ring or three condensed ring of O, S and N at least one ring carbon atom wherein, and wherein N can be randomly by H, C
1-4Acyl group or C
1-4Alkyl replaces;
" heterocyclic radical " expression contains the non-aromatic carbocyclic ring of 3-, 4-, 5-, 6-or 7-unit ring, one of them, two or three ring carbon atoms be selected from the heteroatoms displacement of O, S, N, wherein N can be randomly by H, C
1-4Acyl group or C
1-4Alkyl replaces, and therefore ring carbon atom is randomly formed carbonyl or thiocarbonyl by ketone group or the replacement of sulfo-ketone group.
2. hydrate according to claim 1 or solvolyte, wherein:
R
5For-H, and
R
10For-H.
3. hydrate according to claim 1 or solvolyte, wherein
is singly-bound.
4. hydrate according to claim 1 or solvolyte, wherein Q is O.
5. hydrate according to claim 1 or solvolyte, wherein Q is S, S (O) or S (O)
2
6. hydrate according to claim 1 or solvolyte, wherein K is selected from :-CH
2-,-CH
2CH
2-and-CH (CH
3) CH
2-.
7. hydrate according to claim 1 or solvolyte, wherein K is a key.
8. hydrate according to claim 1 or solvolyte, wherein A and B are-CH
2-.
9. hydrate according to claim 1 or solvolyte, wherein A is-CH
2CH
2-and B be-CH
2-.
10. hydrate according to claim 1 or solvolyte, wherein A and B are-CH
2CH
2-.
11. hydrate according to claim 1 or solvolyte, wherein A is-CH
2-and B be-CH
2CH
2CH
2-.
12. hydrate according to claim 1 or solvolyte, wherein E is that CH and D are N-R
2
13. hydrate according to claim 1 or solvolyte, wherein E is that CH and D are CHR
2
14. hydrate according to claim 1 or solvolyte, wherein R
2Be formula (C) group
Wherein
G be .-NHC (O)-,-NH-,-NHC (O) O-,-CH
2NHC (O)-or key; And
R
24For randomly being selected from C separately by 1 to 2
1-4Alkoxyl group and C
1-7The substituted C of the substituting group of alkyl
1-8Alkyl or heteroaryl.
15. hydrate according to claim 1 or solvolyte, wherein R
2Be formula (C) group
Wherein:
G is-CR
25R
26C (O)-,-C (O) ,-C (O) NR
25-,-C (O) O-,-C (S) NR
25-,-CR
25R
26-or key, wherein R
25And R
26Independent separately is H or C
1-8Alkyl; And
R
24For separately randomly by 1 to 5 substituted C of substituting group that is selected from following group
1-8Alkyl, C
3-7Naphthenic base, phenyl, heteroaryl or heterocyclic radical: C
1-4Alkoxyl group, C
1-7Alkyl, C
1-4Alkylamino, amino, carbonyl-C
1-6Alkoxyl group, carboxyl, C
3-7Naphthenic base, C
2-8Dialkyl amido, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, halogen, heteroaryl, heterocyclic radical, hydroxyl and nitro,
Wherein said C
1-4Alkoxyl group, C
1-7Alkyl, C
1-4Alkylamino, heteroaryl and phenyl are randomly replaced by 1 to 5 substituting group that is selected from following group separately: C
1-4Alkoxyl group, carbonyl-C
1-6-alkoxyl group, carboxamide groups, carboxyl, C
3-7Naphthenic base, halogen, heterocyclic radical and phenyl.
16. hydrate according to claim 1 or solvolyte, wherein R
2For-C (O) OR
24And R
24For separately randomly by 1 to 5 substituted C of substituting group that is selected from following group
1-8Alkyl, C
3-7Naphthenic base, phenyl, heteroaryl or heterocyclic radical: C
1-4Alkoxyl group, C
1-7Alkyl, C
1-4Alkyl sulphonyl, amino, carbonyl-C
1-6-alkoxyl group, carboxyl, cyanic acid, C
3-7Naphthenic base, C
2-8Dialkyl amido, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, halogen, heteroaryl, heterocyclic radical, hydroxyl, phenyl, phenoxy and-SO
3H, wherein said C
1-7Alkyl, phenyl and phenoxy randomly are selected from amino, C by 1 to 5 separately
1-4The substituting group of halogen alkoxyl group and heterocyclic radical replaces.
17. hydrate according to claim 1 or solvolyte, wherein R
2For-C (O) OR
24And R
24For separately randomly by 1 to 5 substituted C of substituting group that is selected from following group
1-8Alkyl or C
3-7Naphthenic base: C
1-4Alkoxyl group, C
1-7Alkyl, C
1-4Alkyl sulphonyl, carboxyl, cyanic acid, C
3-7Naphthenic base, C
2-8Dialkyl amido, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, halogen, heteroaryl, heterocyclic radical, hydroxyl, phenyl, phenoxy and-SO
3H.
18. hydrate according to claim 1 or solvolyte, wherein R
2For-C (O) OR
24And R
24Be C
1-8Alkyl or C
3-7Naphthenic base, wherein said C
3-7Naphthenic base is randomly replaced by 1 to 5 substituting group that is selected from following group: C
1-4Alkoxyl group, C
1-7Alkyl, carboxyl, C
2-8Dialkyl amido and halogen.
19. hydrate according to claim 1 or solvolyte, wherein R
2For-C (O) OR
24And R
24Be C
1-8Alkyl or C
3-7Naphthenic base.
20. hydrate according to claim 1 or solvolyte, wherein R
2For-C (O) OR
24And R
24For separately randomly by 1 to 5 substituted C of substituting group that is selected from following group
1-8Alkyl, C
3-7Naphthenic base, phenyl, heteroaryl or heterocyclic radical: C
2-6Thiazolinyl, C
1-4Alkoxyl group, C
1-7Alkyl, C
1-4Alkyl sulphonyl, amino, carbonyl-C
1-6-alkoxyl group, carboxyl, cyanic acid, C
3-7Naphthenic base, C
2-8Dialkyl amido, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, halogen, heteroaryl, heterocyclic radical, hydroxyl, phenyl, phenoxy and-SO
3H,
Wherein said C
1-7Alkyl, phenyl and phenoxy randomly are selected from amino, C by 1 to 5 separately
1-4The substituting group of halogen alkoxyl group and heterocyclic radical replaces.
21. hydrate according to claim 1 or solvolyte, wherein R
2For-C (O) OR
24And R
24For separately randomly by 1 to 5 substituted C of substituting group that is selected from following group
1-8Alkyl, heteroaryl or heterocyclic radical: H, C
1-4Alkoxyl group, C
1-7Alkyl, amino, carboxyl, halogen, heteroaryl, hydroxyl, phenoxy and-SO
3H, wherein said alkyl and phenoxy randomly are selected from amino, C by 1 to 5 separately
1-4The substituting group of halogen alkoxyl group and heterocyclic radical replaces.
22. hydrate according to claim 1 or solvolyte, wherein Ar
1For randomly by R
13, R
14, R
15, R
16And R
17Substituted phenyl;
R wherein
13Be selected from: C
1-6Acyl group sulfoamido, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkylamino, C
1-6Alkyl carboxamide groups, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, amino, carbamyl imino-, carboxamide groups, carboxyl, cyanic acid, C
2-6Dialkyl amido, C
1-4Alkylhalide group, halogen, heterocyclic radical, heterocyclic radical-oxygen base, heterocyclic radical-carbonyl, heteroaryl, heteroaryl carbonyl and sulfoamido,
And wherein said C
1-6Acyl group sulfoamido, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkylamino, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, carbamyl imino-, C
2-6Dialkyl amido, heterocyclic radical, heterocyclic radical-carbonyl and heteroaryl are randomly replaced by 1 to 5 substituting group that independently is selected from following group separately: C
1-6Acyl group sulfoamido, C
1-4Alkoxyl group, C
1-7Alkyl, C
1-4Alkyl carboxamide groups, C
1-4Alkyl sulphonyl, carboxyl, C
3-7Cycloalkyloxy, C
2-6Dialkyl amido, C
2-6Dialkyl group carboxamide groups, heteroaryl, heterocyclic radical, hydroxyl, phenyl and phosphonato,
And wherein said C
1-7Alkyl and C
1-4The alkyl carboxamide groups randomly is selected from C by 1 to 5 separately
1-4The substituting group of alkoxyl group and hydroxyl replaces; And
R
14, R
15, R
16And R
17Independently be selected from separately: C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkyl carboxamide groups, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, carboxamide groups, cyanic acid, C
1-4Alkylhalide group and halogen.
23. hydrate according to claim 1 or solvolyte, wherein Ar
1For randomly by R
13, R
14, R
15, R
16And R
17Substituted phenyl;
R wherein
13Be selected from: C
1-6Acyl group sulfoamido, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkylamino, C
1-6Alkyl carboxamide groups, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, carbamyl imino-, carboxamide groups, carboxyl, cyanic acid, C
2-6Dialkyl amido, halogen, heterocyclic radical, heterocyclic radical-oxygen base, heterocyclic radical-carbonyl, heteroaryl, heteroaryl carbonyl and sulfoamido,
And wherein said C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkylamino, C
1-6Alkyl carboxamide groups, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, carbamyl imino-, C
2-6Dialkyl amido, heterocyclic radical, heterocyclic radical-carbonyl and heteroaryl are randomly replaced by 1 to 5 substituting group that independently is selected from following group separately: C
1-6Acyl group sulfoamido, C
1-4Alkoxyl group, C
1-7Alkyl, C
1-4Alkyl carboxamide groups, C
1-4Alkyl sulphonyl, carboxyl, C
2-6Dialkyl amido, C
2-6Dialkyl group carboxamide groups, heteroaryl, heterocyclic radical, hydroxyl, phenyl and phosphonato, and wherein said C
1-7Alkyl and C
1-4The alkyl carboxamide groups randomly is selected from C by 1 to 5 separately
1-4The substituting group of alkoxyl group and hydroxyl replaces; And
R
14, R
15, R
16And R
17Independently be selected from separately: C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkyl carboxamide groups, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, carboxamide groups, cyanic acid and halogen.
24. hydrate according to claim 1 or solvolyte, wherein Ar
1For randomly by R
13, R
14, R
15, R
16And R
17Substituted phenyl;
R wherein
13Be selected from: C
1-6Acyl group sulfoamido, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkylamino, C
1-6Alkyl carboxamide groups, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, carbamyl imino-, carboxamide groups, carboxyl, cyanic acid, C
2-6Dialkyl amido, halogen, heterocyclic radical, heterocyclic radical-oxygen base, heterocyclic radical-carbonyl, heteroaryl, heteroaryl carbonyl and sulfoamido,
And wherein said C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkylamino, C
1-6Alkyl carboxamide groups, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, carbamyl imino-, C
2-6Dialkyl amido, heterocyclic radical, heterocyclic radical-carbonyl and heteroaryl are randomly replaced by 1 to 5 substituting group that independently is selected from following group separately: C
1-6Acyl group sulfoamido, C
1-4Alkoxyl group, C
1-7Alkyl, C
1-4Alkyl carboxamide groups, C
1-4Alkyl sulphonyl, carboxyl, C
2-6Dialkyl amido, C
2-6Dialkyl group carboxamide groups, heteroaryl, heterocyclic radical, hydroxyl, phenyl and phosphonato,
And wherein said C
1-7Alkyl and C
1-4The alkyl carboxamide groups randomly is selected from C by 1 to 5 separately
1-4The substituting group of alkoxyl group and hydroxyl replaces; And
R
14, R
15, R
16And R
17Independently be selected from C separately
1-8Alkyl and halogen.
25. hydrate according to claim 1 or solvolyte, wherein Ar
1For randomly by R
13, R
14, R
15And R
16Substituted pyridyl;
R wherein
13Be selected from C
1-6Acyl group sulfoamido, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkylamino, C
1-6Alkyl carboxamide groups, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, amino, carbamyl imino-, carboxamide groups, carboxyl, cyanic acid, C
2-6Dialkyl amido, halogen, heterocyclic radical, heterocyclic radical-oxygen base, heterocyclic radical-carbonyl, heteroaryl and sulfoamido,
And wherein said C
1-6Acyl group sulfoamido, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkylamino, C
1-4Alkylsulfonamido, alkyl sulphonyl, C
1-4Alkylthio, carbamyl imino-, C
2-6Dialkyl amido, heterocyclic radical, heterocyclic radical-carbonyl and heteroaryl are randomly replaced by 1 to 5 substituting group that independently is selected from following group separately: C
1-6Acyl group sulfoamido, C
1-4Alkoxyl group, C
1-7Alkyl, C
1-4Alkyl carboxamide groups, C
1-4Alkyl sulphonyl, carboxyl, C
3-7Cycloalkyloxy, C
2-6Dialkyl amido, C
2-6Dialkyl group carboxamide groups, heteroaryl, heterocyclic radical, hydroxyl, phenyl and phosphonato,
And wherein said C
1-7Alkyl and C
1-4The alkyl carboxamide groups randomly is selected from C by 1 to 5 separately
1-4The substituting group of alkoxyl group and hydroxyl replaces; And
R
14, R
15And R
16Independently be selected from separately: C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkyl carboxamide groups, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, carboxamide groups, cyanic acid and halogen.
26. hydrate according to claim 1 or solvolyte, wherein Ar
1For randomly by R
13, R
14, R
15And R
16Substituted pyridyl;
R wherein
13Be selected from: C
1-6Acyl group sulfoamido, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkylamino, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, amino, C
2-6Dialkyl amido, halogen, heterocyclic radical and sulfoamido,
And wherein said C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkylamino, alkyl sulphonyl, C
1-4Alkylthio, C
2-6Dialkyl amido and heterocyclic radical are randomly replaced C by 1 to 5 substituting group that independently is selected from following group separately
1-6Acyl group sulfoamido, C
1-4Alkoxyl group, C
1-4Alkyl sulphonyl, C
3-7Cycloalkyloxy, heteroaryl, hydroxyl, phenyl and phosphonato; And
R
14, R
15And R
16Independently be selected from separately: C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkyl carboxamide groups, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, carboxamide groups, cyanic acid and halogen.
27. hydrate according to claim 1 or solvolyte, wherein Ar
1For randomly by R
13, R
14, R
15And R
16Substituted pyridyl,
R wherein
13Be selected from: C
1-6Acyl group sulfoamido, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkylamino, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, amino, C
2-6Dialkyl amido, halogen, heterocyclic radical and sulfoamido,
And wherein said C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkylamino, alkyl sulphonyl, C
1-4Alkylthio, C
2-6Dialkyl amido and heterocyclic radical are independent separately randomly to be replaced by 1 to 5 substituting group that independently is selected from following group: C
1-6Acyl group sulfoamido, C
1-4Alkoxyl group, C
1-4Alkyl sulphonyl, C
3-7Cycloalkyloxy, heteroaryl, hydroxyl, phenyl and phosphonato; And
R
14, R
15And R
16Independently be selected from C separately
1-8Alkyl and halogen.
28. hydrate according to claim 1 or solvolyte, wherein said compound has following molecular formula:
29. hydrate according to claim 1 or solvolyte, wherein said compound molecule formula be suc as formula shown in (H7),
Wherein:
A is-CH
2-or-CH
2CH
2-;
B is-CH
2-,-CH
2CH
2-or-CH
2CH
2CH
2-;
E is CH;
D is N-R
2
K is-CH
2-,-CH
2CH
2-,-CH (CH
3) CH
2-or key;
Q is O, S, S (O) or S (O)
2
R
5Be H or CH
3
R
10Be H or CH
3,
R
2For-CR
25R
26C (O) R
24,-C (O) R
24,-C (O) R
25R
24,-R
24,-C (O) OR
24-C (S) NR
25R
24Or-CR
25R
26R
24,
Wherein
R
24For separately randomly by 1 to 5 substituted C of substituting group that is selected from following group
1-8Alkyl, C
3-7Naphthenic base, phenyl, heteroaryl or heterocyclic radical C
2-6Thiazolinyl, C
1-4Alkoxyl group, C
1-7Alkyl, C
1-4Alkyl sulphonyl, amino, carbonyl-C
1-6-alkoxyl group, carboxyl, cyanic acid, C
3-7Naphthenic base, C
2-8Dialkyl amido, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, halogen, heteroaryl, heterocyclic radical, hydroxyl, phenyl, phenoxy and-SO
3H,
Wherein said C
1-7Alkyl, phenyl and phenoxy are randomly replaced by 1 to 5 substituting group that is selected from following group separately: amino, C
1-4Halogen alkoxyl group and heterocyclic radical; And
R
25And R
26Independent separately is H or C
1-8Alkyl; And
Ar
1For randomly by R
13R
14, R
15, R
16And R
17Substituted phenyl or pyridyl; Wherein
R
13Be selected from: C
1-6Acyl group sulfoamido, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkylamino, C
1-6Alkyl carboxamide groups, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, amino, carbamyl imino-, carboxamide groups, carboxyl, cyanic acid, C
2-6Dialkyl amido, halogen, heterocyclic radical, heterocyclic radical-oxygen base, heterocyclic radical-carbonyl, heteroaryl and sulfoamido,
And wherein said C
1-6Acyl group sulfoamido, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkylamino, C
1-4Alkylsulfonamido, alkyl sulphonyl, C
1-4Alkylthio, carbamyl imino-, C
2-6Dialkyl amido, heterocyclic radical, heterocyclic radical-carbonyl and heteroaryl are randomly replaced by 1 to 5 substituting group that independently is selected from following group separately: C
1-6Acyl group sulfoamido, C
1-4Alkoxyl group, C
1-7Alkyl, C
1-4Alkyl carboxamide groups, C
1-4Alkyl sulphonyl, carboxyl, C
3-7Cycloalkyloxy, C
2-6Dialkyl amido, C
2-6Dialkyl group carboxamide groups, heteroaryl, heterocyclic radical, hydroxyl, phenyl and phosphonato;
And wherein said C
1-7Alkyl and C
1-4The alkyl carboxamide groups randomly is selected from C by 1 to 5 separately
1-4The substituting group of alkoxyl group and hydroxyl replaces;
R
14, R
15, R
16And R
17Independently be selected from separately: C
1-4Alkoxyl group, C
1-4Alkyl carboxamide groups, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, carboxamide groups, cyanic acid and halogen.
30. hydrate according to claim 1 or solvolyte, wherein said compound molecule formula be suc as formula shown in (H7),
Wherein:
A and B are-CH
2CH
2-;
E is CH;
D is N-R
2
K is a key;
Q is O;
R
5And R
10All be H;
R
2For-C (O) OR
24, R wherein
24For separately randomly by 1 to 5 substituted C of substituting group that is selected from following group
1-8Alkyl or C
3-7Naphthenic base: C
1-4Alkoxyl group, C
1-7Alkyl, C
1-4Alkyl sulphonyl, amino, carbonyl-C
1-6-alkoxyl group, carboxyl, cyanic acid, C
3-7Naphthenic base, C
2-8Dialkyl amido, C
1-4Halogen alkoxyl group, C
1-4Alkylhalide group, halogen, heteroaryl, heterocyclic radical, hydroxyl, phenyl and phenoxy; And
Ar
1For randomly by R
13, R
14, R
15, R
16And R
17Substituted phenyl or pyridyl, wherein
R
13Be selected from: C
1-6Acyl group sulfoamido, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkylamino, C
1-6Alkyl carboxamide groups, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, amino, carbamyl imino-, carboxamide groups, carboxyl, cyanic acid, C
2-6Dialkyl amido, halogen, heterocyclic radical, heterocyclic radical-oxygen base, heterocyclic radical-carbonyl, heteroaryl and sulfoamido,
And wherein said C
1-6Acyl group sulfoamido, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkylamino, C
1-4Alkylsulfonamido, alkyl sulphonyl, C
1-4Alkylthio, carbamyl imino-, C
2-6Dialkyl amido, heterocyclic radical, heterocyclic radical-carbonyl and heteroaryl are randomly replaced by 1 to 5 substituting group that independently is selected from following group separately: C
1-6Acyl group sulfoamido, C
1-4Alkoxyl group, C
1-7Alkyl, C
1-4Alkyl carboxamide groups, C
1-4Alkyl sulphonyl, carboxyl, C
3-7Cycloalkyloxy, C
2-6Dialkyl amido, C
2-6Dialkyl group carboxamide groups, heteroaryl, heterocyclic radical, hydroxyl, phenyl and phosphonato,
And wherein said C
1-7Alkyl and C
1-4The alkyl carboxamide groups randomly is selected from C by 1 to 5 separately
1-4The substituting group of alkoxyl group and hydroxyl replaces; And
R
14, R
15, R
16And R
17Independently be selected from separately: C
1-4Alkoxyl group, C
1-8Alkyl and halogen.
31. hydrate according to claim 1 or solvolyte, wherein:
A and B are-CH
2CH
2-;
E is CH:
D is N-R
2,
K is a key;
Q is O;
R
5And R
10All be H,
R
2For-C (O) OR
24, R wherein
24Be C
1-8Alkyl or C
3-7Naphthenic base;
Ar
1For separately randomly by R
13, R
14, R
15, R
16And R
17Substituted phenyl, 3-pyridyl or 2-pyridyl;
R wherein
13Be selected from: C
1-6Acyl group sulfoamido, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkylamino, C
1-6Alkyl carboxamide groups, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, carbamyl imino-, carboxamide groups, carboxyl, cyanic acid, C
2-6Dialkyl amido, halogen, heterocyclic radical, heterocyclic radical-oxygen base, heterocyclic radical-carbonyl, heteroaryl, heteroaryl carbonyl and sulfoamido,
And wherein said C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkylamino, C
1-6Alkyl carboxamide groups, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphonyl, C
1-4Alkylthio, carbamyl imino-, C
2-6Dialkyl amido, heterocyclic radical, heterocyclic radical-carbonyl and heteroaryl are randomly replaced by 1 to 5 substituting group that independently is selected from following group separately: C
1-6Acyl group sulfoamido, C
1-4Alkoxyl group, C
1-7Alkyl, C
1-4Alkyl carboxamide groups, C
1-4Alkyl sulphonyl, carboxyl, C
2-6Dialkyl amido, C
2-6Dialkyl group carboxamide groups, heteroaryl, heterocyclic radical, hydroxyl, phenyl and phosphonato,
And wherein said C
1-7Alkyl and C
1-4The alkyl carboxamide groups randomly is selected from C by 1 to 5 separately
1-4The substituting group of alkoxyl group and hydroxyl replaces, and
R
14, R
15, R
16And R
17Independent separately is CH
3Or F.
32. hydrate according to claim 31 or solvolyte, wherein R
2Be selected from the group that forms by following group: methoxycarbonyl, ethoxy carbonyl, isopropoxy carbonyl, positive propoxy carbonyl, n-butoxy carbonyl, tert-butoxycarbonyl, isobutoxy carbonyl and n-pentyloxy carbonyl.
33. hydrate according to claim 31 or solvolyte, wherein R
13Be selected from: sulfamyl, ethanoyl sulfamyl, propionyl group sulfamyl, butyryl radicals sulfamyl, pentanoyl sulfamyl, methylsulfonyl, ethylsulfonyl, third-1-alkylsulfonyl, methylol, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxyl-butyl, phosphonato methyl, 2-phosphonato-ethyl, 3-phosphonato-propyl group and 4-phosphonato-butyl.
34. hydrate according to claim 1 or solvolyte, wherein said compound is selected from following compounds:
(A1) 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-t-butyl formate;
(A2) 4-[1-(4-methylsulfonyl-phenyl)-3-methyl isophthalic acid H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-t-butyl formate;
(A3) 4-[1-(4-methylsulfonyl-phenyl)-3,6-dimethyl--1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-t-butyl formate;
(A4) 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-tetryl formate;
(A5) 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-isopropyl formate;
(A6) 1-(4-methylsulfonyl-phenyl)-4-(piperidin-4-yl oxygen base)-1H-pyrazolo [3,4-d] pyrimidine;
(A7) { 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-pyridin-3-yl-ketone;
(A8) (3-fluoro-phenyl)-{ 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone;
(A9) (the 1-tertiary butyl-5-methyl isophthalic acid H-pyrazoles-4-yl)-{ 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone;
(A10) (the 5-tertiary butyl-2-methyl-2H-pyrazole-3-yl)-{ 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [34-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone;
(A14) furans-2-base-{ 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone;
(A15) { 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-(1-methyl isophthalic acid H-pyrroles-2-yl)-ketone;
(A16) 2-{4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-1-pyridin-3-yl-ethyl ketone;
(A17) 2-{4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-1-pyridine-2-base-ethyl ketone;
(A18) { 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-(5-methyl-pyridin-3-yl)-ketone,
(A19) { 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-(2-methyl-pyridin-3-yl)-ketone;
(A20) { 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-(6-methyl-pyridin-3-yl)-ketone;
(A21) { 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-(5-methyl-isoxazole-3-bases)-ketone;
(A22) 2-{4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-1-thiophene-2-base-ethyl ketone;
(A23) 4-(1-benzyl-azetidine-3-base oxygen base)-1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine,
(A25) 1-{4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-3,3-dimethyl--Ding-2-ketone,
(A26) { 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-pyrazine-2-base-ketone;
(A27) { 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-(5-methyl-pyrazine-2-yl)-ketone;
(A28) { 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-pyrimidine-5-base-ketone;
(A29) { 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-pyridazine-4-base-ketone;
(A30) { 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-thiophene-2-base-ketone;
(A31) (3,4-dimethyl--isoxazole-5-bases)-{ 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone;
(A32) 3-tert.-butoxy-1-{4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-third-1-ketone;
(A33) (3-{4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-3-ketone group-propyl group)-methyl-t-butyl carbamate;
(A34) { 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-(6-trifluoromethyl-pyridin-3-yl)-ketone;
(A37) { 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-(4-methyl-[1,2,3] thiadiazoles-5-yl)-ketone;
(A38) (3,5-dimethyl--isoxazole-4-bases)-{ 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone;
(A39) (2,5-dimethyl--2H-pyrazole-3-yl)-{ 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone;
(A40) 1-{4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-2-(3-methyl-isoxazole-5-bases)-ethyl ketone;
(A41) 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-thiocarbonic acid SOH pyridin-4-yl acid amides;
(A45) 4-[1-(4-(2-methylsulfonyl-ethyl)-phenyl]-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-t-butyl formate,
(A46) 4-[1-(3,5-couple-trifluoromethyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-t-butyl formate,
(A47) 3-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-azetidine-1-isopropyl formate:
(A48) 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-butyl formate,
(A49) 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-propyl formate;
(A50) 4-[1-(3-fluoro-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-t-butyl formate,
(A51) 4-[1-(2,4-two fluoro-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-t-butyl formate;
(A60) { 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-cyclohexyl }-t-butyl carbamate,
(A62) { 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-(4-trifluoromethyl-pyridin-3-yl)-ketone;
(A63) 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-cyclohexyl formate;
(A64) 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-formic acid tetrahydrochysene-pyrans-4-base ester,
(A65) 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-formic acid ring pentyl ester;
(A66) 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-formic acid tetrahydrochysene-furans-3-base ester;
(A67) 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-formic acid tetrahydrochysene-furans-3-base ester
(A68) 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-formic acid tetrahydrochysene-thiapyran-4-base ester;
(A69) 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-formic acid ring butyl ester;
(A70) (the 6-tertiary butyl-pyridin-3-yl)-4-[1-{4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone;
(A74) 4-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-t-butyl formate;
(A79) 4-{1-[2-(2-dimethylamino-oxyethyl group)-4-methylsulfonyl-phenyl]-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base }-piperidines-1-t-butyl formate;
(A81) 4-1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-pyridine carboxylic acid-3-ylmethyl ester,
(A82) 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-formic acid 2-pyridin-3-yl-ethyl ester;
(A83) 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-formic acid 3-pyridin-3-yl-propyl ester:
(A84) 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-formic acid 2-dimethylamino-ethyl ester;
(A86) 4-[1-(2,5-two fluoro-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-t-butyl formate; With
(A89) 4-[6-dimethylamino-1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [34-d] pyrimidine-4-base oxygen base]-piperidines-1-t-butyl formate.
35. hydrate according to claim 1 or solvolyte, wherein said compound is selected from following compounds:
(A94) 2-{4-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-1-(4-trifluoromethoxy-phenyl)-ethyl ketone;
(A95) 2-{4-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-1-(3-fluoro-phenyl)-ethyl ketone;
(A96) 2-{4-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-1-pyridine-2-base-ethyl ketone;
(A97) (2,5-dimethyl--furans-3-yl)-{ 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone;
(A100) 4-[1-(2-dimethylamino-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-t-butyl formate;
(A102) 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base sulfenyl]-piperidines-1-t-butyl formate;
(A103) 4-{2-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-ethyl }-piperazine-1-ethyl formate;
(A104) 4-{2-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-propyl group }-piperazine-1-ethyl formate;
(A105) 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-sulfinyl]-piperidines-1-t-butyl formate,
(A106) 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-alkylsulfonyl]-piperidines-1-t-butyl formate;
(A107) 4-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base sulfenyl]-piperidines-1-t-butyl formate,
(A108) 4-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base sulfenyl]-piperidines-1-butyl formate;
(A109) 4-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base sulfenyl]-piperidines-1-formic acid 2-methoxyl group-ethyl ester;
(A110) 4-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base sulfenyl]-piperidines-1-formic acid 3,3-dimethyl--butyl ester;
(A111) 4-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base sulfenyl]-piperidines-1-formic acid 4-methyl-pentyl ester,
(A112) 4-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base sulfenyl]-piperidines-1-formic acid cyclopropyl methyl esters;
(A113) 4-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base sulfenyl 1]-piperidines-1-formic acid cyclobutyl methyl esters;
(A114) 4-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base sulfenyl]-piperidines-1-formic acid 2-cyclopropyl-ethyl ester;
(A115) (5-bromo-furans-2-yl)-{ 4-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base sulfenyl]-piperidines-1-yl }-ketone;
(A116) { 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-(5-morpholine-4-ylmethyl-furans-2-yl)-ketone;
(A117) 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-pentyl formate;
(A118) 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-formic acid 1-ethyl-propyl ester;
(A119) 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-formic acid 2-ethyl-butyl ester;
(A120) 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-formic acid cyclopentyl methyl esters,
(A121) 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-formic acid 2-tetramethyleneimine-1-base-ethyl ester,
(A122) 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-formic acid 2-morpholine-4-base-ethyl ester;
(A123) 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-ethyl formate;
(A124) 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-formic acid 2,2-dimethyl--propyl ester;
(A125) (5-butyl-pyridine-2-yl)-{ 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone;
(A129) 4-[1-(2-fluoro-4-methylsulfonyl-phenyl-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-isopropyl formate;
(A130) 5 '-fluoro-4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-3,4,5,6-tetrahydrochysene-2H-[1,2 '] dipyridyl;
(A131) 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-5 '-methyl-3,4,5,6-tetrahydrochysene-2H-[1,2] dipyridyl;
(A132) 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-6 '-trifluoromethyl-3,4,5,6-tetrahydrochysene-2H-[1,2 '] dipyridyl;
(A135) (4-ethyl-pyridine-2-yl)-{ 4-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone,
(A136) 1-(2-fluoro-4-methylsulfonyl-phenyl)-4-[1-(3-sec.-propyl-[1,2,4] oxadiazole-5-ylmethyls)-tetramethyleneimine-3-base oxygen base]-1H-pyrazolo [3,4-d] pyrimidine;
(A137) 1-(2-fluoro-4-methylsulfonyl-phenyl)-4-[1-(3-sec.-propyl-[1,2,4] oxadiazole-5-ylmethyls)-piperidin-4-yl oxygen base]-1H-pyrazolo [3,4-d] pyrimidine;
(A139) (5-bromo-pyridin-3-yl)-{ 4-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone;
(A140) 3-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-tetramethyleneimine-1-t-butyl formate;
(A143) (6-chloro-pyridin-3-yl)-{ 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone;
(A144) (5-chloro-pyridin-3-yl)-{ 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone,
(A145) { 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-(1-methyl-3-Trifluoromethyl-1 H-pyrazoles-4-yl)-ketone;
(A146) (2-chloro-pyridin-4-yl)-{ 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone;
(A147) (4-hydroxyl-3-methoxyl group-phenyl)-{ 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone;
(A148) (4-chloro-3-nitro-phenyl)-{ 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone;
(A149) 1-{4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-3-methyl-Ding-1-ketone;
(A150) { 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-(6-pyrazol-1-yl-pyridin-3-yl)-ketone;
(A151) (2-hydroxyl-pyridin-3-yl)-{ 4-[1-(4-methylsulfonyl-phenyl)-H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone;
(A152) (5,6-two chloro-pyridin-3-yls)-{ 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone,
(A153) (5-bromo-pyridin-3-yl)-{ 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone;
(A154) 5-{4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-carbonyl }-nicotinic acid;
(A155) (1H-imidazol-4 yl)-{ 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone;
(A156) 3-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-tetramethyleneimine-1-t-butyl formate,
(A157) { 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-(6-tetramethyleneimine-1-base-pyridin-3-yl)-ketone;
(A158) (6-isobutyl amino-pyridine-3-yl)-{ 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone;
(A159) (6-ethylamino-pyridin-3-yl)-{ 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone;
(A161) (6-isopropylamino-pyridin-3-yl)-{ 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone;
(A162) [6-(1-ethyl-third amino)-pyridin-3-yl]-{ 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone;
(A163) { 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-[6-(1-propyl group-Ding is amino)-pyridin-3-yl]-ketone;
(A164) 5-benzyloxy-2-{4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-carbonyl }-pyrans-4-ketone;
(A165) benzo [c] isoxazole-3-base-{ 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone;
(A166) (4-chloro-pyridine-2-yl)-4-[1-{4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone;
(A167) (4-iodo-pyridine-2-yl)-{ 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone;
(A168) 1-{4-[1-{4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-Ding-2-ketone;
(A169) 2-(5-bromo-pyridin-3-yl)-1-{4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ethyl ketone;
(A170) (6-fluoro-pyridine-2-yl)-{ 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone;
(A171) (5-fluoro-pyridine-2-yl)-{ 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone;
(A172) (6-chloro-pyridine-2-yl)-{ 4-[1--(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone;
(A173) (2-chloro-5-fluoro-pyridin-3-yl)-{ 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone,
(A175) { 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-(6-methyl-pyridine-2-yl)-ketone;
(A176) 5-{4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-carbonyl }-the cigarette eyeball,
(A177) { 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-(4-methoxyl group-pyridine-2-yl)-ketone,
(A178) (2-fluoro-pyridin-4-yl)-{ 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone;
(A179) (2-fluoro-pyridin-3-yl)-{ 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone;
(A180) (6-fluoro-pyridin-3-yl)-{ 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [34-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone;
(A181) { 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-(4-methoxyl group-thiene-3-yl-)-ketone;
(A182) 2-{4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-carbonyl }-pyrans-4-ketone,
(A183) (5-ethyl-pyridine-2-yl)-{ 4-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone;
(A184) (4-oxyethyl group-phenyl)-{ 4-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone;
(A185) { 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-(5-pyridine-2-base-thiophene-2-yl)-ketone,
(A186) (5-amino-pyridine-2-yl)-{ 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone;
(A187) (5-amino-pyridine-2-yl)-{ 4-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone;
(A188) { 4-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-[5-(3-methyl-Ding is amino)-pyridine-2-yl]-ketone;
(A189) { 4-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-(4-trifluoromethoxy-phenyl)-ketone;
(A190) (5-butyl-pyridine-2-yl)-{ 4-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone;
(A191) (5-ethylamino-pyridine-2-yl)-{ 4-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone;
(A192) { 4-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-(5-isopropoxy methyl-pyridine-2-yl)-ketone;
(A193) (4-difluoro-methoxy-phenyl)-{ 4-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone;
(A194) { 4-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-(5-isopropoxy-pyridine-2-yl)-ketone;
(A195) 5-{4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-carbonyl }-pyridine-2-methyl-formiate;
(A196) { 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ETHYLE ACETATE;
(A197) { 4-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-(3-trifluoromethoxy-phenyl)-ketone;
(A198) 1-(2-fluoro-4-methylsulfonyl-phenyl)-4-[1-(3-sec.-propyl-[1,2,4] oxadiazole-5-yls)-piperidin-4-yl oxygen base]-1H-pyrazolo [3,4-d] pyrimidine;
(A199) 1-(4-chloro-phenyl)-2-{4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ethyl ketone;
(A200) 2-{4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-1-(3-trifluoromethyl-phenyl)-ethyl ketone;
(A201) 4-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-5 '-isopropoxy-3,4,5,6-tetrahydrochysene-2H-[1,2 '] dipyridyl;
(A202) 1-(4-methylsulfonyl-phenyl)-4-[1-(4-trifluoromethoxy-phenyl)-piperidin-4-yl oxygen base]-1H-pyrazolo [3,4-d] pyrimidine;
(A203) 1-(2-fluoro-4-methylsulfonyl-phenyl)-4-[1-(4-trifluoromethoxy-phenyl)-piperidin-4-yl oxygen base]-1H-pyrazolo [3,4-d] pyrimidine;
(A204) 1-(4-chloro-3-methyl-phenyl)-2-{4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ethyl ketone;
(A205) 1-(3,4-two chloro-phenyl)-2-{4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ethyl ketone;
(A206) 5 '-bromo-4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-3,4,5,6-tetrahydrochysene-2H-[1,2 '] dipyridyl;
(A207) 1-(2-fluoro-4-methylsulfonyl-phenyl)-4-[1-(3-trifluoromethoxy-phenyl)-piperidin-4-yl oxygen base]-1H-pyrazolo [3,4-d] pyrimidine;
(A208) 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-5 '-trifluoromethyl-3,4,5,6-tetrahydrochysene-2H-[1,2 '] dipyridyl;
(A209) 1-(2,4-dimethoxy-phenyl)-2-{4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ethyl ketone;
(A210) 1-(4-difluoro-methoxy-phenyl)-2-{4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ethyl ketone;
(A211) 1-(4-diethylin-phenyl)-2-{4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ethyl ketone;
(A212) (2-{4-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-5-methyl-pyrimidine-4-yl)-dimethyl--amine;
(A213) 1-(2-fluoro-4-methylsulfonyl-phenyl)-4-[1-(5-methyl-4-tetramethyleneimine-1-base-pyrimidine-2-base)-piperidin-4-yl oxygen base]-1H-pyrazolo [3,4-d] pyrimidine;
(A214) 4-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base sulfenyl]-piperidines-1-isopropyl formate,
(A215) 4-[1-(2-methyl-4-third amino-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-isopropyl formate;
(A216) 4-[1-(4-isopropylamino-2-methyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-isopropyl formate;
(A217) 4-[1-(2-methyl-4-morpholine-4-base-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-isopropyl formate;
(A218) 4-{1-[4-(2-methoxyl group-ethylamino)-2-methyl-phenyl]-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base }-piperidines-1-isopropyl formate,
(A219) 4-(1-{4-[(2-methylsulfonyl-ethyl)-methyl-amino]-2-methyl-phenyl }-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base)-piperidines-1-isopropyl formate;
(A220) 4-[1-(4-bromo-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-isopropyl formate;
(A221) 4-[1-(4-third amino-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-isopropyl formate;
(A222) 4-[1-(4-isopropylamino-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-isopropyl formate;
(A224) 4-(1-{2-methyl-4-[(tetrahydrochysene-furans-2-ylmethyl)-amino]-phenyl }-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base)-piperidines-1-isopropyl formate,
(A226) 4-{1-[4-(2-dimethylamino-ethylamino)-2-methyl-phenyl]-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base }-piperidines-1-isopropyl formate;
(A227) 4-[1-(4-morpholine-4-base-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-isopropyl formate;
(A229) 4-[1-(2-fluoro-4-morpholine-4-base-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-isopropyl formate;
(A230) 4-[1-(2-fluoro-4-isopropylamino-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-isopropyl formate;
(A231) 4-(1-{4-[(2-methylsulfonyl-ethyl)-methyl-amino]-phenyl }-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base)-piperidines-1-isopropyl formate;
(A232) 4-{1-[4-(2-methoxyl group-ethylamino)-phenyl]-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base }-piperidines-1-isopropyl formate.
(A233) 4-(1-{4-[(tetrahydrochysene-furans-2-ylmethyl)-amino]-phenyl }-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base)-piperidines-1-isopropyl formate:
(A235) 4-[1-(4-amino-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-isopropyl formate;
(A237) 4-[1-(5-ethyl-pyrimidine-2-base)-piperidin-4-yl sulfenyl]-1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine;
(A238) 1-(2-fluoro-4-methylsulfonyl-phenyl)-4-(piperidin-4-yl oxygen base)-1H-pyrazolo [3,4-d] pyrimidine;
(A239) 4-[1-(2-fluoro-4-sulfamyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-isopropyl formate;
(A240) 4-[1-(2-fluoro-4-propionyl group sulfamyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-isopropyl formate;
(A241) 4-[1-(4-cyanic acid-2-fluoro-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-isopropyl formate;
(A242) 1-(2,5-two fluoro-4-methoxyl group-phenyl)-[4-(3-sec.-propyl-[1,2,4] oxadiazole-5-yl)-cyclohexyloxy]-1H-pyrazolo [3,4-d] pyrimidine;
(A243) 4-[1-(2,5-two fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-isopropyl formate,
(A244) 4-[1-(4-fluoro-6-methoxyl group-pyridin-3-yl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-isopropyl formate;
(A245) 4-[1-(6-methoxyl group-2-methyl-pyridin-3-yl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-isopropyl formate,
(A246) 4-[1-(2,5-two fluoro-4-sulfamyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-isopropyl formate;
(A247) 4-[1-(2-fluoro-4-hydroxyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-isopropyl formate;
(A248) 3-fluoro-4-{4-[1-(3-sec.-propyl-[1,2,4] oxadiazole-5-yls)-piperidin-4-yl oxygen base]-pyrazolo [3,4-d] pyrimidine-1-yl }-N-propionyl group-benzsulfamide;
(A249) 3-fluoro-4-{4-[1-(3-sec.-propyl-[1,2,4] oxadiazole-5-yls)-piperidin-4-yl oxygen base]-pyrazolo [3,4-d] pyrimidine-1-yl }-benzonitrile;
(A250) 3-fluoro-4-{4-[1-(3-sec.-propyl-[1,2,4] oxadiazole-5-yls)-piperidin-4-yl oxygen base]-pyrazolo [3,4-d] pyrimidine-1-yl }-benzsulfamide;
(A251) 1-(2,5-two fluoro-4-methylsulfonyl-phenyl)-4-[1-(3-sec.-propyl-[1,2,4] oxadiazole-5-yl)-piperidin-4-yl oxygen base]-1H-pyrazolo [3,4-d] pyrimidine;
(A252) 1-(4-fluoro-6-methoxyl group-pyridin-3-yl)-4-[1-(3-sec.-propyl-[1,2,4] oxadiazole-5-yls)-piperidin-4-yl oxygen base]-1H-pyrazolo [3,4-d] pyrimidine;
(A253) 4-[1-(3-sec.-propyl-[1,2,4] oxadiazole-5-yls)-piperidin-4-yl oxygen base]-1-(6-methoxyl group-2-methyl-pyridin-3-yl)-1H-pyrazolo [3,4-d] pyrimidine,
(A254) 2,5-two fluoro-4-{4-[1-(3-sec.-propyl-[1,2,4] oxadiazole-5-yl)-piperidin-4-yl oxygen base]-pyrazolo [3,4-d] pyrimidine-1-yl }-benzsulfamide;
(A255) 1-(2-fluoro-4-methylsulfonyl-phenyl)-4-[4-(3-sec.-propyl-[1,2,4] oxadiazole-5-yls)-cyclohexyloxy]-1H-pyrazolo [3,4-d] pyrimidine;
(A256) 3-fluoro-4-{4-[4-(3-sec.-propyl-[1,2,4] oxadiazole-5-yls)-cyclohexyloxy]-pyrazolo [3,4-d] pyrimidine-1-yl }-N-propionyl group-benzsulfamide;
(A257) 3-fluoro-4-{4-[4-(3-sec.-propyl-[1,2,4] oxadiazole-5-yls)-cyclohexyloxy]-pyrazolo [3,4-d] pyrimidine-1-yl }-benzonitrile;
(A258) 3-fluoro-4-{4-[4-{3-sec.-propyl-[1,2,4] oxadiazole-5-yls)-cyclohexyloxy]-pyrazolo [3,4-d] pyrimidine-1-yl }-benzsulfamide;
(A259) 1-(2,5-two fluoro-4-methylsulfonyl-phenyl)-4-[4-(3-sec.-propyl-[1,2,4] oxadiazole-5-yl)-cyclohexyloxy]-1H-pyrazolo [3,4-d] pyrimidine;
(A260) 1-(4-fluoro-6-methoxyl group-pyridin-3-yl)-4-[4-(3-sec.-propyl-[1,2,4] oxadiazole-5-yls)-cyclohexyloxy]-1H-pyrazolo [3,4-d] pyrimidine;
(A261) 4-[4-(3-sec.-propyl-[1,2,4] oxadiazole-5-yls)-cyclohexyloxy]-1-(6-methoxyl group-2-methyl-pyridin-3-yl)-1H-pyrazolo [3,4-d] pyrimidine;
(A262) 2,5-two fluoro-4-{4-[4-(3-sec.-propyl-[1,2,4] oxadiazole-5-yl)-cyclohexyloxy]-pyrazolo [3,4-d] pyrimidine-1-yl }-benzsulfamide,
(A263) 4-[1-(2-fluoro-4-methoxyl group-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-isopropyl formate;
(A264) 4-[1-(4-difluoro-methoxy-2-fluoro-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-isopropyl formate,
(A265) 4-[1-(2-fluoro-4-trifluoromethoxy-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-isopropyl formate;
(A266) 4-[1-(2,5-two fluoro-4-methoxyl group-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-isopropyl formate.
(A267) 3-fluoro-4-{4-[1-(3-sec.-propyl-[1,2,4] oxadiazole-5-yls)-piperidin-4-yl oxygen base]-pyrazolo [3,4-d] pyrimidine-1-yl }-phenol;
(A268) 1-(2-fluoro-4-methoxyl group-phenyl)-4-[1-(3-sec.-propyl-[1,2,4] oxadiazole-5-yls)-piperidin-4-yl oxygen base]-1H-pyrazolo [3,4-d] pyrimidine;
(A269) 1-(4-difluoro-methoxy-2-fluoro-phenyl)-4-[1-(3-sec.-propyl-[1,2,4] oxadiazole-5-yls)-piperidin-4-yl oxygen base]-1H-pyrazolo [3,4-d] pyrimidine;
(A270) 1-(2-fluoro-4-trifluoromethoxy-phenyl)-4-[1-(3-sec.-propyl-[1,2,4] oxadiazole-5-yls)-piperidin-4-yl oxygen base]-1H-pyrazolo [3,4-d] pyrimidine;
(A271) 1-(2,5-two fluoro-4-methoxyl group-phenyl)-4-[1-(3-sec.-propyl-[1,2,4] oxadiazole-5-yl)-piperidin-4-yl oxygen base]-1H-pyrazolo [3,4-d] pyrimidine;
(A272) 3-fluoro-4-{4-[4-(3-sec.-propyl-[1,2,4] oxadiazole-5-yls)-cyclohexyloxy]-pyrazolo [3,4-d] pyrimidine-1-yl }-phenol;
(A273) 1-(2-fluoro-4-methoxyl group-phenyl)-4-[4-(3-sec.-propyl-[1,2,4] oxadiazole-5-yls)-cyclohexyloxy]-1H-pyrazolo [3,4-d] pyrimidine,
(A274) 1-(4-difluoro-methoxy-2-fluoro-phenyl)-4-[4-(3-sec.-propyl-[1,2,4] oxadiazole-5-yls)-cyclohexyloxy]-1H-pyrazolo [3,4-d] pyrimidine; With
(A275) 1-(2-fluoro-4-trifluoromethoxy-phenyl)-4-[4-(3-sec.-propyl-[1,2,4] oxadiazole-5-yls)-cyclohexyloxy]-1H-pyrazolo [3,4-d] pyrimidine.
36. hydrate according to claim 1 or solvolyte, wherein said compound is selected from following compounds:
(A1) 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-t-butyl formate.
37. hydrate according to claim 1 or solvolyte, wherein said compound is selected from following compounds:
(A5) 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-isopropyl formate.
38. hydrate according to claim 1 or solvolyte, wherein said compound is selected from following compounds:
(A38) (3,5-dimethyl--isoxazole-4-bases)-{ 4-[1-(4-methylsulfonyl-phenyl)-1H-pyrazolo [34-d] pyrimidine-4-base oxygen base]-piperidines-1-yl }-ketone.
39. hydrate according to claim 1 or solvolyte, wherein said compound is selected from following compounds:
(A107) 4-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base sulfenyl]-piperidines-1-t-butyl formate.
40. hydrate according to claim 1 or solvolyte, wherein said compound is selected from following compounds:
(A129) 4-[1-(2-fluoro-4-methylsulfonyl-phenyl-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-isopropyl formate.
41. hydrate according to claim 1 or solvolyte, wherein said compound is selected from following compounds
(A214) 4-[1-(2-fluoro-4-methylsulfonyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base sulfenyl]-piperidines-1-isopropyl formate.
42. hydrate according to claim 1 or solvolyte, wherein said compound is selected from following compounds:
(A239) 4-[1-(2-fluoro-4-sulfamyl-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-isopropyl formate.
43. hydrate according to claim 1 or solvolyte, wherein said compound is selected from following compounds:
(A241) 4-[1-(4-cyanic acid-2-fluoro-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base]-piperidines-1-isopropyl formate.
44. hydrate according to claim 1 or solvolyte, wherein said compound is selected from following compounds
(A249) 3-fluoro-4-{4-[1-(3-sec.-propyl-[1,2,4] oxadiazole-5-yls)-piperidin-4-yl oxygen base]-pyrazolo [3,4-d] pyrimidine-1-yl }-benzonitrile.
45. hydrate according to claim 1 or solvolyte, wherein said compound is selected from following compounds:
(A250) 3-fluoro-4-{4-[1-(3-sec.-propyl-[1,2,4] oxadiazole-5-yls)-piperidin-4-yl oxygen base]-pyrazolo [3,4-d] pyrimidine-1-yl }-benzsulfamide.
46. a medical composition, it comprises at least a according to described hydrate of arbitrary claim or solvolyte among the claim 1-45 and a pharmaceutically acceptable supporting agent.
47. a method of making medical composition, it comprises and mixes with a pharmaceutically acceptable supporting agent according to described hydrate of arbitrary claim or solvolyte among the claim 1-45 at least a.
48. the purposes according to described hydrate of arbitrary claim or solvolyte among the claim 1-45, said hydrate or solvolyte are to be used to make the medicine that is used to prevent or treat following illness: type i diabetes, type ii diabetes, improper glucose tolerance, insulin resistance, hyperglycemia, hyperlipidaemia, hypertriglyceridemia, hypercholesterolemia, hyperlipemia or X syndromes.
49. the purposes according to described hydrate of arbitrary claim or solvolyte among the claim 1-45, said hydrate or solvolyte are to be used to make the medicine that is used to prevent or treat type ii diabetes.
50. the purposes according to arbitrary described hydrate or solvolyte among the claim 1-45, said hydrate or solvolyte are to be used to make the medicine that is used to reduce individual ingestion of food.
51. the purposes according to arbitrary described hydrate or solvolyte among the claim 1-45, said hydrate or solvolyte are to be used to make the medicine that is used to bring out individual satiety.
52. the purposes according to arbitrary described hydrate or solvolyte among the claim 1-45, said hydrate or flux thing are to be used to make be used to control or reduce the medicine that whose body weight increases.
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| Application Number | Priority Date | Filing Date | Title |
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| US48744303P | 2003-07-14 | 2003-07-14 | |
| US60/487,443 | 2003-07-14 | ||
| US51064403P | 2003-10-10 | 2003-10-10 | |
| US60/510,644 | 2003-10-10 |
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